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Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline Stefan R. Bornstein (chair), Bruno Allolio, Wiebke Arlt, Andreas Barthel, Andrew Don-Wauchope, Gary D. Hammer, Eystein S. Husebye, Deborah P. Merke, M. Hassan Murad, Constantine A. Stratakis, and David J. Torpy* Objective: This clinical practice guideline addresses the diagnosis and treatment of primary adrenal insufficiency. Participants: The Task Force included a chair, selected by The Clinical Guidelines Subcommittee of the Endocrine Society, eight additional clinicians experienced with the disease, a methodologist, and a medical writer. The co-sponsoring associations (European Society of Endocrinology and the American Association for Clinical Chemistry) had participating members. The Task Force received no corporate funding or remuneration in connection with this review. Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to determine the strength of recom- mendations and the quality of evidence. Consensus Process: The evidence used to formulate recommendations was derived from two commissioned systematic reviews as well as other published systematic reviews and studies iden- tified by the Task Force. The guideline was reviewed and approved sequentially by the Endocrine Society’s Clinical Guidelines Subcommittee and Clinical Affairs Core Committee, members respond- ing to a web posting, and the Endocrine Society Council. At each stage, the Task Force incorporated changes in response to written comments. Conclusions: We recommend diagnostic tests for the exclusion of primary adrenal insufficiency in all patients with indicative clinical symptoms or signs. In particular, we suggest a low diagnostic (and therapeutic) threshold in acutely ill patients, as well as in patients with predisposing factors. This is also recommended for pregnant women with unexplained persistent nausea, fatigue, and hypotension. We recommend a short corticotropin test (250 g) as the “gold standard” diagnostic tool to establish the diagnosis. If a short corticotropin test is not possible in the first instance, we recommend an initial screening procedure comprising the measurement of morning plasma ACTH and cortisol levels. Diagnosis of the underlying cause should include a validated assay of autoan- tibodies against 21-hydroxylase. In autoantibody-negative individuals, other causes should be sought. We recommend once-daily fludrocortisone (median, 0.1 mg) and hydrocortisone (15–25 mg/d) or cortisone acetate replacement (20 –35 mg/d) applied in two to three daily doses in adults. In children, hydrocortisone (8 mg/m 2 /d) is recommended. Patients should be educated about stress dosing and equipped with a steroid card and glucocorticoid preparation for parenteral emergency administration. Follow-up should aim at monitoring appropriate dosing of corticoste- roids and associated autoimmune diseases, particularly autoimmune thyroid disease. (J Clin En- docrinol Metab 101: 364 –389, 2016) ISSN Print 0021-972X ISSN Online 1945-7197 Printed in USA Copyright © 2016 by the Endocrine Society Received March 18, 2015. Accepted December 2, 2015. First Published Online December 13, 2015 * Author Affiliations are shown at the bottom of the next page. Abbreviations: APS, autoimmune polyendocrine syndrome; CAH, congenital adrenal hy- perplasia; CBG, cortisol-binding globulin; CT, computer tomography; DHEA, dehydroepi- androsterone; DHEAS, DHEA sulfate; HRQoL, health-related quality of life; LC-MS/MS, liquid chromatography/tandem mass spectrometry; PAI, primary adrenal insufficiency. SPECIAL FEATURE Clinical Practice Guideline 364 press.endocrine.org/journal/jcem J Clin Endocrinol Metab, February 2016, 101(2):364 –389 doi: 10.1210/jc.2015-1710 The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 22 January 2017. at 20:38 For personal use only. No other uses without permission. . All rights reserved.
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Page 1: Diagnosis and Treatment of Primary Adrenal Insufficiency ... › pediatrics › documents › ACTHStim-Endoso… · 1.3 In patients with severe adrenal insufficiency symptoms or adrenal

Diagnosis and Treatment of Primary AdrenalInsufficiency: An Endocrine Society Clinical PracticeGuideline

Stefan R. Bornstein (chair), Bruno Allolio, Wiebke Arlt, Andreas Barthel,Andrew Don-Wauchope, Gary D. Hammer, Eystein S. Husebye,Deborah P. Merke, M. Hassan Murad, Constantine A. Stratakis,and David J. Torpy*

Objective: This clinical practice guideline addresses the diagnosis and treatment of primary adrenal

insufficiency.

Participants: The Task Force included a chair, selected by The Clinical Guidelines Subcommittee of

the Endocrine Society, eight additional clinicians experienced with the disease, a methodologist,

and a medical writer. The co-sponsoring associations (European Society of Endocrinology and the

American Association for Clinical Chemistry) had participating members. The Task Force received

no corporate funding or remuneration in connection with this review.

Evidence: This evidence-based guideline was developed using the Grading of Recommendations,

Assessment, Development, and Evaluation (GRADE) system to determine the strength of recom-

mendations and the quality of evidence.

Consensus Process: The evidence used to formulate recommendations was derived from two

commissioned systematic reviews as well as other published systematic reviews and studies iden-

tified by the Task Force. The guideline was reviewed and approved sequentially by the Endocrine

Society’s Clinical Guidelines Subcommittee and Clinical Affairs Core Committee, members respond-

ing to a web posting, and the Endocrine Society Council. At each stage, the Task Force incorporated

changes in response to written comments.

Conclusions: We recommend diagnostic tests for the exclusion of primary adrenal insufficiency in

all patients with indicative clinical symptoms or signs. In particular, we suggest a low diagnostic

(and therapeutic) threshold in acutely ill patients, as well as in patients with predisposing factors.

This is also recommended for pregnant women with unexplained persistent nausea, fatigue, and

hypotension. We recommend a short corticotropin test (250 �g) as the “gold standard” diagnostic

tool to establish the diagnosis. If a short corticotropin test is not possible in the first instance, we

recommend an initial screening procedure comprising the measurement of morning plasma ACTH

and cortisol levels. Diagnosis of the underlying cause should include a validated assay of autoan-

tibodies against 21-hydroxylase. In autoantibody-negative individuals, other causes should be

sought. We recommend once-daily fludrocortisone (median, 0.1 mg) and hydrocortisone (15–25

mg/d) or cortisone acetate replacement (20–35 mg/d) applied in two to three daily doses in adults.

In children, hydrocortisone (�8 mg/m2/d) is recommended. Patients should be educated about

stress dosing and equipped with a steroid card and glucocorticoid preparation for parenteral

emergency administration. Follow-up should aim at monitoring appropriate dosing of corticoste-

roids and associated autoimmune diseases, particularly autoimmune thyroid disease. (J Clin En-

docrinol Metab 101: 364–389, 2016)

ISSN Print 0021-972X ISSN Online 1945-7197Printed in USACopyright © 2016 by the Endocrine SocietyReceived March 18, 2015. Accepted December 2, 2015.First Published Online December 13, 2015

* Author Affiliations are shown at the bottom of the next page.Abbreviations: APS, autoimmune polyendocrine syndrome; CAH, congenital adrenal hy-perplasia; CBG, cortisol-binding globulin; CT, computer tomography; DHEA, dehydroepi-androsterone; DHEAS, DHEA sulfate; HRQoL, health-related quality of life; LC-MS/MS,liquid chromatography/tandem mass spectrometry; PAI, primary adrenal insufficiency.

S P E C I A L F E A T U R E

C l i n i c a l P r a c t i c e G u i d e l i n e

364 press.endocrine.org/journal/jcem J Clin Endocrinol Metab, February 2016, 101(2):364–389 doi: 10.1210/jc.2015-1710

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Summary of Recommendations

1.0 Who should be tested and how?1.1 We recommend diagnostic testing to exclude pri-

mary adrenal insufficiency (PAI) in acutely ill patients withotherwise unexplained symptoms or signs suggestive ofPAI (volume depletion, hypotension, hyponatremia, hy-perkalemia, fever, abdominalpain,hyperpigmentationor,especially in children, hypoglycemia). (1�QQQE)

1.2 We recommend confirmatory testing with the cor-ticotropin stimulation test in patients with clinical symp-toms or signs suggesting PAI when the patient’s conditionand circumstance allow. (1�QQQQ)

1.3 In patients with severe adrenal insufficiencysymptoms or adrenal crisis, we recommend immediatetherapy with iv hydrocortisone at an appropriate stressdose prior to the availability of the results of diagnostictests. (1�QQQE)

2.0 Optimal diagnostic tests2.1 We suggest the standard dose (250 �g for adults and

children �2 y of age, 15 �g/kg for infants, and 125 �g forchildren �2 y of age) iv corticotropin stimulation (30 or 60min) test over other existing diagnostics tests to establishthe diagnosis of adrenal insufficiency. Peak cortisol levelsbelow 500 nmol/L (18 �g/dL) (assay dependent) at 30 or60 minutes indicate adrenal insufficiency. (2�QQEE)

2.2 We suggest the low-dose (1 �g) corticotropin testfor diagnosis of PAI only when the substance itself is inshort supply. (2�QQEE)

2.3 If a corticotropin stimulation test is not feasible, wesuggest using a morning cortisol �140 nmol/L (5 �g/dL)in combination with ACTH as a preliminary test sugges-tive of adrenal insufficiency (until confirmatory testingwith corticotropin stimulation is available). (2�QEEE)

2.4 We recommend measurement of plasma ACTH toestablish PAI. The sample can be obtained at the same timeas the baseline sample in the corticotropin test or pairedwith the morning cortisol sample. In patients with con-firmed cortisol deficiency, a plasma ACTH �2-fold theupper limit of the reference range is consistent with PAI.(1�QQQE)

2.5 We recommend the simultaneous measurement ofplasma renin and aldosterone in PAI to determine the pres-ence of mineralocorticoid deficiency. (1�QQQE)

2.6 We suggest that the etiology of PAI should be de-termined in all patients with confirmed disease. (For di-agnostic workup, see Table 2 and Figure 1.) (Ungradedbest practice recommendation)

3.0 Treatment of primary adrenal insufficiency inadults

Glucocorticoid replacement regimen3.1 We recommend glucocorticoid therapy in all pa-

tients with confirmed PAI. (1�QQQQ)3.2 We suggest using hydrocortisone (15–25 mg) or cor-

tisone acetate (20–35 mg) in two or three divided oral dosesper day; the highest dose should be given in the morning atawakening, the next either in the early afternoon (2 h afterlunch; two-dose regimen) or at lunch and afternoon (three-dose regimen). Higher frequency regimens and size-baseddosing may be beneficial in individual cases. (2�QQEE)

3.3 As an alternative to hydrocortisone, we suggest us-ing prednisolone (3–5 mg/d), administered orally once ortwice daily, especially in patients with reduced compli-ance. (2�QEEE)

3.4 We suggest against using dexamethasone for thetreatment of PAI because of risk of Cushingoid side effectsdue to difficulties in dose titration. (2�QQEE)

3.5 We suggest monitoring glucocorticoid replacementusing clinical assessment including body weight, posturalblood pressure, energy levels, signs of frank glucocorticoidexcess. (2�QQQE)

3.6 We suggest against hormonal monitoring of gluco-corticoid replacement and to adjust treatment only basedon clinical response. (2�QQQE)

Mineralocorticoid replacement in PAI3.7 We recommend that all patients with confirmed

aldosterone deficiency receive mineralocorticoid replace-ment with fludrocortisone (starting dose, 50–100 �g inadults) and not restrict their salt intake. (1�QQQQ)

3.8 We recommend monitoring mineralocorticoid re-placement primarily based on clinical assessment (saltcraving, postural hypotension, or edema), and blood elec-trolyte measurements. (1�QQQE)

3.9 In patients who develop hypertension while receiv-ing fludrocortisone, we suggest reducing the dose offludrocortisone. (2�QEEE)

Medizinische Klinik und Poliklinik III (S.R.B., A.B.), Universitätsklinikum Dresden, 01307 Dresden, Germany; Department of Endocrinology and Diabetes (S.R.B.), King’s College London,London WC2R 2LS, United Kingdom; Department of Internal Medicine I (B.A.), Endocrine and Diabetes Unit, University Hospital Würzburg, 97080 Würzburg, Germany; ComprehensiveHeart Failure Center (B.A.), University of Würzburg, 97080 Würzburg, Germany; Centre for Endocrinology, Diabetes, and Metabolism (W.A.), University of Birmingham, Birmingham B152TT, United Kingdom; Endokrinologikum Ruhr (A.B.), 44866 Bochum, Germany; Department of Pathology and Molecular Medicine (A.D.-W.), McMaster University, Hamilton, ON L8S4L8, Canada; Hamilton Regional Laboratory Medicine Program (A.D.-W.), Hamilton, ON L8N 4A6, Canada; Department of Internal Medicine (G.D.H.), Division of Metabolism, Endo-crinology, and Diabetes, and Cancer Center, University of Michigan, Ann Arbor, Michigan 48109; Department of Clinical Science, University of Bergen, and Department of Medicine,Haukeland University Hospital (E.S.H.), 5021 Bergen, Norway; National Institutes of Health Clinical Center (D.P.M.), Bethesda, Maryland 20814; Mayo Clinic, Division of Preventive Medicine(M.H.M.), Rochester, Minnesota 55905; Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.A.S.), National Institutes of Health, Bethesda, Maryland20892; and Endocrine and Metabolic Unit (D.J.T.), Royal Adelaide Hospital, University of Adelaide, Adelaide SA 5000, Australia

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3.10 If blood pressure remains uncontrolled, we sug-gest initiating antihypertensive treatment and continuingfludrocortisone. (2�QEEE)

Dehydroepiandrosterone replacement3.11 We suggest a trial of dehydroepiandrosterone

(DHEA) replacement in women with PAI and low libido,depressive symptoms, and/or low energy levels despiteotherwise optimized glucocorticoid and mineralocorti-coid replacement. (2�QQEE)

3.12 We suggest an initial period of 6 months of DHEAreplacement. If the patient does not report a sustained,beneficial effect of replacement after 6 months, the DHEAshould be discontinued. (2�QQEE)

3.13 We suggest monitoring DHEA replacement bymeasuring morning serum DHEA sulfate (DHEAS) levels(aiming at the midnormal range) before the intake of thedaily DHEA replacement dose. (2�QQEE)

Treatment during pregnancy3.14 We suggest that pregnant patients with PAI be

monitored for clinical symptoms and signs of glucocorti-coid over- and under-replacement (eg, normal weightgain, fatigue, postural hypotension or hypertension, hy-perglycemia), with at least one review per trimester. (Un-graded best practice statement)

3.15 We suggest that, based on the individual clinicalcourse, an increase in hydrocortisone dose should be im-plemented, in particular during the third trimester. (Un-graded best practice statement)

3.16 In pregnant women with PAI, we suggest usinghydrocortisone over cortisone acetate, prednisolone, orprednisone (2�QQEE) and recommend against usingdexamethasone because it is not inactivated in the pla-centa. (1�QQEE)

3.17 We recommend hydrocortisone stress dosing dur-ing the active phase of labor, similar to that used in majorsurgical stress. (1�QQEE)

Treatment and monitoring during childhood3.18 In children with PAI, we suggest treatment with

hydrocortisone in three or four divided doses (total start-ing daily dose of 8 mg/m2 body surface area) over othertypes of glucocorticoid replacement therapies, with dosesadjusted according to individual need. (2�QQEE)

3.19 In children with PAI, we suggest avoiding syn-thetic, long-acting glucocorticoids (eg, prednisolone,dexamethasone). (2�QQEE)

3.20 We suggest monitoring glucocorticoid replace-ment by clinical assessment, including growth velocity,body weight, blood pressure, and energy levels. (Ungradedbest practice statement)

3.21 In children with PAI and confirmed aldosteronedeficiency, we recommend treatment with fludrocortisone(starting dosage, 100 �g/d). For infants, we recommendsodium chloride supplements in the newborn period andup to the age of 12 months. (1�QQEE)

4.0 Management and prevention of adrenal crisisin patients with PAI

4.1 We recommend that patients with suspected adre-nal crisis should be treated with an immediate parenteralinjection of 100 mg (50 mg/m2 for children) hydrocorti-sone, followed by appropriate fluid resuscitation and 200mg (50–100 mg/m2 for children) of hydrocortisone/24hours (via continuous iv therapy or 6 hourly injection);age- and body surface-appropriate dosing is required inchildren (see Table 3). (1�QQQE)

4.2 If hydrocortisone is unavailable, we suggest pred-nisolone as an alternative. Dexamethasone is the least-preferred alternative and should only be given if no otherglucocorticoid is available. (2�QQEE)

4.3 For the prevention of adrenal crisis, we suggest ad-justing glucocorticoid dose according to severity of illnessor magnitude of the stressor. (2�QQEE)

4.4 We suggest patient education concerning glucocor-ticoid adjustments in stressful events and adrenal crisis-prevention strategies including parenteral self- or lay-ad-ministration of emergency glucocorticoids. (Ungradedbest practice statement)

4.5 We recommend that all patients should be equippedwith a steroid emergency card and medical alert identifi-cation to inform health personnel of the need for increasedglucocorticoid doses to avert or treat adrenal crisis and theneed of immediate parenteral steroid treatment in theevent of an emergency. (Ungraded best practice statement)

4.6 We recommend that every patient should beequipped with a glucocorticoid injection kit for emergencyuse and be educated on how to use it. (Ungraded bestpractice statement)

5.0 Additional monitoring requirement5.1 We suggest that adults and children with PAI be

seen by an endocrinologist or a healthcare provider withendocrine expertise at least annually. Infants should beseen at least every 3 to 4 months. (Ungraded best practicestatement)

5.2 We suggest that PAI patients be evaluated annuallyfor symptoms and signs of over- and under-replacement.(Ungraded best practice statement)

5.3 We suggest periodic screening for autoimmune dis-eases known to be more prevalent in PAI patients in whomautoimmune origin of PAI has not been excluded. Theoptimal frequency of screening is unknown but can be

366 Bornstein (chair) et al Guidelines on Primary Adrenal Insufficiency J Clin Endocrinol Metab, February 2016, 101(2):364–389

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done annually. These conditions include thyroid disease,diabetes mellitus, premature ovarian failure, celiac dis-ease, and autoimmune gastritis with vitamin B12 defi-ciency. (2�QQEE)

5.4 We suggest patient education about increasing thedosage of glucocorticoids during intercurrent illness, fe-ver, and stress. This education includes identification ofprecipitating symptoms and signs and how to act in im-pending adrenal crisis. (Ungraded best practice statement)

5.5 We suggest genetic counseling for patients with PAIdue to monogenic disorders. (Ungraded best practicestatement)

General Introduction

PAI is defined by the inability of the adrenal cortex toproduce sufficient amounts of glucocorticoids and/or min-eralocorticoids. PAI is a severe and potentially life-threat-ening condition due to the central role of these hormonesin energy, salt, and fluid homeostasis. PAI was first de-scribed by Thomas Addison (1) and is therefore commonlytermed Addison’s disease. Cortisol deficiency results in adecrease in feedback to the hypothalamic-pituitary axisand subsequent enhanced stimulation of the adrenal cor-tex by elevated levels of plasma ACTH. Consequent todisruption of adrenal mineralocorticoid synthesis, reninrelease by the juxtaglomerular cells of the kidneys in-creases. This is of clinical, diagnostic, and therapeutic rel-evance because PAI needs to be distinguished from sec-

ondary adrenocortical insufficiency due to insufficientproduction of ACTH and without impact on the renin-angiotensin-aldosterone system.

The signs of PAI are mainly based on the deficiency ofgluco- and mineralocorticoids and the resultant weightloss, orthostatic hypotension due to dehydration, hypo-natremia, hyperkalemia, changes in blood count (anemia,eosinophilia, lymphocytosis), and hypoglycemia (summa-rized in Table 1). Enhanced secretion of ACTH and otherpro-opiomelanocortin peptides often leads to the charac-teristic hyperpigmentation of the skin and mucous mem-branes. In women, loss of adrenal androgens results in lossof axillary and pubic hair. Except for salt craving, thesymptoms of PAI are rather nonspecific and include weak-ness, fatigue, musculoskeletal pain, weight loss, abdomi-nal pain, depression, and anxiety. As a result, the diagnosisis frequently delayed, resulting in a clinical presentationwith an acute life-threatening adrenal crisis (2). Even withtreatment, the health-related quality of life (HRQoL) inpatients with Addison’s disease receiving standard re-placement therapy is often reduced (3, 4). Moreover, long-term HRQoL in these patients appears to be inversely re-lated to the delay in establishing the diagnosis after diseaseonset, emphasizing the importance of recognizing the dis-ease early (5, 6). This is complicated by the fact that PAIis a rare disease with a reported prevalence of about 100to 140 cases per million and an incidence of 4:1 000 000per year in Western societies (7–10). Nevertheless, recenthealth insurance data from Germany report an increasing

Table 1. Clinical Features of Adrenal Insufficiency and Adrenal Crisis

Symptoms SignsRoutine LaboratoryTests

Adrenal insufficiencyFatigue Hyperpigmentation (primary only), particularly of sun-exposed

areas, skin creases, mucosal membranes, scars, areola ofbreast

Hyponatremia

Weight loss Low blood pressure with increased postural drop HyperkalemiaPostural dizziness Failure to thrive in children Uncommon: hypoglycemia,

hypercalcemiaAnorexia, abdominal discomfort

Adrenal crisisSevere weakness HyponatremiaSyncope Hypotension HyperkalemiaAbdominal pain, nausea, vomiting;

may mimic acute abdomenAbdominal tenderness/guarding Hypoglycemia

Back pain Reduced consciousness, delirium HypercalcemiaConfusion

Most symptoms are nonspecific and present chronically, often leading to delayed diagnosis. Hyponatremia and, later, hyperkalemia are oftentriggers to diagnosis, requiring biochemical confirmation of adrenal insufficiency. Hyperpigmentation is a specific sign, but it is variably present inindividuals and must be compared with the patient’s background pigmentation, such as that in siblings. Adrenal crisis is a medical emergency withhypotension, marked acute abdominal symptoms, and marked laboratory abnormalities, requiring immediate treatment. Continuing effort toprevent adrenal crisis is integral to patient management. Additional symptoms and signs may arise from the underlying cause of adrenalinsufficiency, eg, associated autoimmune disorders, neurological features of adrenoleukodystrophy, or disorders that may lead to adrenalinfiltration.

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prevalence, particularly in females (11). The most com-mon cause of PAI is autoimmunity (up to 90% in Westerncountries), followed by infectious diseases such as tuber-culosis, adrenalectomy, neoplasia, and various geneticcauses; the last are more likely to be present and diagnosedin children. Moreover, due to the growing number ofchronically and severely ill patients requiring chronic in-tensive care that includes multiple concomitant pharma-cological therapies, additional iatrogenic factors (such asadrenal hemorrhage related to anticoagulants, inhibitionof cortisol synthesis by aminoglutethimide or etomidate,activation of glucocorticoid metabolism by anticonvul-sants like phenytoin or phenobarbital, or antibiotics likerifampicin) increasingly contribute to the ultimate mani-festation of PAI (12).

The diagnosis and management of adrenal insuffi-ciency secondary to hypothalamic-pituitary failure havebeen recently discussed in an expert review in this journal(13). Also, the management of congenital adrenal hyper-plasia (CAH) due to steroid 21-hydroxylase deficiency hasbeen comprehensively discussed, and a current clinicalguideline on CAH has been published by the EndocrineSociety (14). Therefore, the current guideline focuses onthe diagnosis and treatment of PAI alone; issues related tosecondary adrenal insufficiency and critical illness-relatedcorticosteroid insufficiency have been excluded. The levelof evidence and strength of recommendations publishedin this guideline were evaluated based on the GRADEsystem.

Method of Development of Evidence-Based Clinical Practice Guidelines

The Clinical Guidelines Subcommittee (CGS) of the En-docrine Society deemed the management of PAI a priorityarea in need of practice guidelines and appointed a TaskForce to formulate evidence-based recommendations. TheTask Force followed the approach recommended by theGrading of Recommendations, Assessment, Develop-ment, and Evaluation (GRADE) group, an internationalgroup with expertise in development of evidence-basedguidelines (15). A detailed description of the gradingscheme has been published elsewhere (16). The Task Forceused the best available research evidence to develop therecommendations. The Task Force also used consistentlanguage and graphical descriptions of both the strengthof a recommendation and the quality of evidence. In termsof the strength of the recommendation, strong recommen-dations use the phrase “we recommend” and the number1, and weak recommendations use the phrase “we sug-gest” and the number 2. Cross-filled circles indicate the

quality of the evidence, such thatQEEEdenotes very low-quality evidence; QQEE, low quality; QQQE, moderatequality; andQQQQ, high quality. The Task Force has con-fidence that persons who receive care according to thestrong recommendations will derive, on average, moregood than harm. Weak recommendations require morecareful consideration of the person’s circumstances, val-ues, and preferences to determine the best course of action.Linked to each recommendation is a description of theevidence and the values that panelists considered in mak-ing the recommendation; in some instances, there areremarks, a section in which panelists offer technical sug-gestions for testing conditions, dosing, and monitoring.These technical comments reflect the best available evi-dence applied to a typical person being treated. Often thisevidence comes from the unsystematic observations of thepanelists and their values and preferences; therefore, theseremarks should be considered suggestions. In this guide-line, the Task Force made several statements to emphasizevarious monitoring and patient education actions neededto prevent the severe morbidity and mortality of adrenalcrisis and reduce medication side effects. These were la-beled as ungraded best practice statements. Direct evi-dence for these statements was either unavailable or notsystematically appraised and was considered out of thescope of this guideline. The intention of these statementsis to draw attention and remind providers of these prin-ciples, and these statements should not be considered asgraded recommendations (17).

The Endocrine Society maintains a rigorous conflict-of-interest review process for the development of clinicalpractice guidelines. All Task Force members must declareany potential conflicts of interest, which are reviewed be-fore they are approved to serve on the Task Force andperiodically during the development of the guideline. Theconflict-of-interest forms are vetted by the CGS before themembers are approved by the Society’s Council to partic-ipate on the guideline Task Force. Participants in theguideline development must include a majority of individ-uals without conflict of interest in the matter under study.Participants with conflicts of interest may participate inthe development of the guideline, but they must have dis-closed all conflicts. The CGS and the Task Force havereviewed all disclosures for this guideline and resolved ormanaged all identified conflicts of interest.

Conflicts of interest are defined by remuneration in anyamount from the commercial interest(s) in the form ofgrants; research support; consulting fees; salary; owner-ship interest (eg, stocks, stock options, or ownership in-terest excluding diversified mutual funds); honoraria orother payments for participation in speakers’ bureaus, ad-visory boards, or boards of directors; or other financial

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benefits. Completed forms are available through the En-docrine Society office.

Funding for this guideline was derived solely from theEndocrine Society, and thus the Task Force received nofunding or remuneration from commercial or otherentities.

Commissioned systematic reviewsThe Task Force commissioned two systematic reviews

and developed an a priori protocol that included a specificsearch strategy, inclusion and exclusion criteria, andmethods of evidence synthesis. The two reviews summa-rized data on patients with both primary and secondaryadrenal insufficiency; however, the Task Force used dataderived from patients with PAI because this was the targetpopulation of this guideline.

The first review compared the diagnostic accuracy ofhigh-dose ACTH vs low-dose ACTH stimulation tests forthe initial diagnosis. Only five studies were available toestimate the diagnostic accuracy of the high-dose ACTHstimulation test in PAI, and there were none for the low-dose ACTH stimulation test. The sensitivity of the high-dose ACTH stimulation test for the diagnosis of PAI was92% (95% confidence interval, 81–97%). Data from 30studies in patients with secondary adrenal insufficiencyshowed no statistically significant difference between low-dose and high-dose ACTH stimulation tests. This evidenceis indirect for the target population of this guideline, whichis PAI patients.

The second review compared various glucocorticoidreplacement regimens in patients with adrenal insuffi-ciency and identified 15 relevant observational studies.Data on mortality, bone density, and incidence of adrenalcrisis were very sparse or unavailable. In terms of HRQoL,there was no statistically significant difference betweenregimens using glucocorticoid dosages equal to or higherthan 30 mg/d of hydrocortisone vs regimens with dosages�30 mg/d. Very low-quality evidence (comparison acrossstudies, methodological limitations, and substantial het-erogeneity) suggested that extended-release and dual-re-lease forms of glucocorticoids may have higher HRQoLscores compared with forms given once, twice, or threetimes daily. This evidence was considered insufficient fordecision-making and required verification in a random-ized trial.

Diagnosis of primary adrenal insufficiencyThe diagnosis of PAI is traditionally based on low

morning cortisol concentrations (measured in serum orplasma) and confirmed by low stimulated cortisol.DHEAS levels (DHEA less so) that are well below thelower limit of normal for age and sex are a useful initial

sign of PAI that should not be overlooked, although theycannot be used in isolation to make the diagnosis of PAIbecause levels may be low in some individuals, especiallyin older age groups, without PAI. In most cases, the diag-nosis is highly likely if the cortisol is �140 nmol/L (5�g/dL) (18) in combination with an ACTH concentration(measured in plasma) elevated more than 2-fold above theupper limit of the reference interval for the specific assay.An ACTH value �66 pmol/L represents a maximum stim-ulus for cortisol secretion (19, 20). For confirmation, acorticotropin stimulation test should be performed inmost cases unless basal results are absolutely unequivocal.

The corticotropin stimulation test is currently regardedas the diagnostic “gold standard” for the diagnosis of pri-mary (but not secondary) adrenal insufficiency because ithas been reasonably well studied and is validated againstthe insulin tolerance test for diagnostic accuracy (21–25).This test is also known as the cosyntropin test, ACTH test,or short Synacthen test; Synacthen is the trade name oftetracosactide, a synthetic peptide consisting of the first 24of the 39 amino acids of the endogenous ACTH peptide.However, there is still some ongoing debate over the def-inition of the cutoff value of cortisol after corticotropinstimulation to exclude PAI (see below). The test is used inclinical practice with different protocols, mainly in theduration of the test procedure, the route of administration(im or iv), and the dose of corticotropin applied (26, 27).Commonly, the standard short corticotropin test is per-formed measuring cortisol levels before and 30 or 60 min-utes after iv (or im) administration of 250 �g corticotropinas bolus injection (28). The standard-dose (250 �g) shortcorticotropin test is a common diagnostic test in clinicalpractice with a high degree of validation. Another varia-tion of the cosyntropin test uses a low-dose 1 �g of cor-ticotropin for adrenal stimulation. However, based on thecurrently available data, the 1-�g test does not providebetter diagnostic accuracy than the 250-�g corticotropintest (29). It should be noted that porcine ACTH is used insome countries, although the evidence for its use is muchless than with synthetic ACTH analogs such as cosyntro-pin (30).

The interpretation of the cosyntropin test is based onthe peak stimulated serum cortisol concentration. The re-sults of the corticotropin test are not significantly affectedby diurnal variations, and the test can therefore be per-formed without time constraints (31, 32). However, cau-tion is required because adrenocortical function test re-sults may be severely affected by rare conditions such ascortisol-binding globulin (CBG) deficiency, glucocorti-coid resistance, and hypersensitivity (33–36).

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1.0 Who should be tested and how?1.1 We recommend diagnostic testing to exclude PAI in

acutely ill patients with otherwise unexplained symptomsor signs suggestive of PAI (volume depletion, hypotension,hyponatremia, hyperkalemia, fever, abdominal pain, hy-perpigmentationor, especially in children,hypoglycemia).(1�QQQE)

1.2 We recommend confirmatory testing with the cor-ticotropin stimulation test in patients with clinical symp-toms or signs suggesting PAI when the patient’s conditionand circumstance allow. (1�QQQQ)

1.3 In patients with severe adrenal insufficiency symp-toms or adrenal crisis, we recommend immediate therapywith iv hydrocortisone at an appropriate stress dose priorto the availability of the results of diagnostic tests.(1�QQQE)

EvidenceSymptoms of adrenal insufficiency or adrenal crisis are

well established by older observational studies and clinicalexperience and are summarized in Table 1. Delayed treat-ment of more severe symptoms will increase morbidityand mortality. Treatment should therefore not be delayedby awaiting the results of cosyntropin testing.

Diagnosis of PAI is challenging due to an insidious on-set of predominantly nonspecific symptoms over monthsor years. Therefore, it is essential to keep the threshold fordiagnostic evaluation low (2, 37). The exclusion of PAI ismainly based on the determination of cortisol concentra-tions in the corticotropin stimulation test.

In acutely sick patients with clinical signs and symp-toms, treatment should not be delayed awaiting test re-sults. It is important to draw blood for diagnostic purposesbefore any steroid treatment is given. A single baselineACTH and cortisol before administration of hydrocorti-sone is essential for diagnosis, or occasionally even acosyntropin stimulation test may be performed, butonly if safe to do so. Confirmatory cosyntropin testingcan be performed after treatment, with temporary ces-sation of glucocorticoid when the patient’s condition isstable (38, 39).

Although it is more elaborate and requires endocrino-logical expertise, the corticotropin stimulation test is asuperior diagnostic test with a higher degree of sensitivityand specificity than determination of morning cortisol andACTH concentrations and is therefore preferred in allpatients considered with the differential diagnosis ofPAI (28, 38).

Other relatively frequent conditions predisposing pa-tients to PAI include certain autoimmune disorders (eg,type 1 diabetes mellitus, autoimmune gastritis/perniciousanemia, and vitiligo) as well as infectious diseases (tuber-

culosis, HIV, cytomegalovirus, candidiasis, histoplasmo-sis) (Table 2). Adrenal enzyme inhibitors (mitotane, ke-toconazole, metyrapone, and etomidate) are examples ofagents that may induce adrenal insufficiency. In addition,a number of drugs such as phenytoin and carbamazepine,mitotane, and St John’s wort may increase metabolism ofcortisol. Therefore, in patients using these agents, the di-agnostic threshold should also be kept low (12).

Plasma cortisol is 80% bound to CBG and 10–15% toalbumin, so disorders that reduce (inflammation, rare ge-netic disorders) or increase CBG levels (estrogen, preg-nancy, mitotane) need to be considered in interpretation ofplasma cortisol levels (36).

The diagnosis of PAI in pregnant women is particularlychallenging due to its extreme rarity, overlapping symp-toms like nausea and hypotension as well as physiologicalchanges (eg, increased cortisol production during preg-nancy; see Section 3.0 and Recommendation 3.14), mak-ing the diagnosis difficult. Because untreated PAI in preg-nant women is associated with a high mortality, whereassufficiently treated patients can expect a normal preg-nancy course and outcome, early recognition and diagno-sis is critical. In addition to a paired sample of cortisol andACTH, the adrenal reserve is appropriately and safely as-sessed in pregnancy by corticotropin stimulation, if indi-cated (40, 41). Interpretation of the diagnostic results re-quires thorough consideration of pregnancy-associatedphysiological changes of adrenocortical function (42). Astrong recommendation for immediate treatment beforethe availability of test results (but after the relevant sam-ples have been procured) is driven by placing high value onpreventing major harm. A practical diagnostic approachto the patient with PAI is summarized in Figure 1 (14).

Technical remarks on diagnostic recommendations1. The range and severity of PAI symptoms can be clas-

sified as indicative of adrenal insufficiency or adrenal cri-sis, as summarized in Table 1.

2. A heightened level of clinical suspicion of adrenalinsufficiency is warranted in patients with compatiblesymptoms who also have disorders associated with thedevelopment of PAI, such as autoimmune disorders orrelevant drugs (major etiologies of PAI summarized inTable 2).

3. There are several situations requiring specific con-sideration because cortisol levels can be expected to bealtered by nonadrenal pathologies. These include criticalillness and pregnancy. In addition, reduced CBG levels inillness and elevated levels in pregnancy may alter the in-terpretation of cortisol levels.

4. Patients with autoimmune disease and systemic dis-orders known to affect the adrenal function or who are on

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drugs (eg, T4) that are known to increase cortisol metab-olism are at increased risk of PAI.

2.0 Optimal diagnostic tests2.1 We suggest the standard dose (250 �g for adults and

children �2 y of age, 15 �g/kg for infants, and 125 �g forchildren �2 y of age) iv corticotropin stimulation (30 or 60min) test over other existing diagnostics tests to establishthe diagnosis of adrenal insufficiency. Peak cortisol levelsbelow 500 nmol/L (18 �g/dL) (assay dependent) at 30 or60 minutes indicate adrenal insufficiency. (2�QQEE)

EvidenceThe exclusion of PAI is mainly based on the determi-

nation of cortisol concentrations in the corticotropin stim-ulation test. There are five primary studies that consideredthe diagnosis of PAI in their populations and also met theinclusion criteria of the systematic review. Using meta-analysis, the sensitivity of the 250-�g corticotropin stim-ulation test using a peak response of cortisol (500 nmol/Lor 18 �g/dL) was 0.92 (95% confidence interval, 0.81–0.97). The cutoff values for exclusion of adrenal insuffi-ciency may vary according to the assay used. Different

Table 2. Major Etiologies of PAI and Associated Features

Etiology Associated Features

AutoimmuneIsolated Not associated with other autoimmune disordersAPS type 1 (APECED) Chronic cutaneous candidiasis, hypoparathyroidismAPS type 2 Autoimmune thyroid disease, type 1 diabetes

Adrenal—infiltration/injuryAdrenal hemorrhage Associated with sepsis, anticoagulants, anti-cardiolipin/lupus anti-coagulant syndromeAdrenal metastases Malignancies: lung, breast, colon, melanoma, lymphomaInfections: adrenalitis Tuberculosis, HIV/AIDS, CMV, candidiasis, histoplasmosis, syphilis, African trypanosomiasis,

paracoccidioidomycosis (eg, in South America)Infiltration Hemochromatosis, primary amyloidosisBilateral adrenalectomy Procedure for intractable Cushing’s syndrome or bilateral pheochromocytoma

CAH: most forms cancause salt loss

Commonest cause of PAI in children (80%); may be diagnosed in older individuals

21-Hydroxylasedeficiency

Commonest type of CAH is 21-hydroxylase deficiency, with associated hyperandrogenism

11�-hydroxylasedeficiency

Hyperandrogenism, hypertension (in older children and adults)

3�-hydroxysteroiddehydrogenase IIdeficiency

Ambiguous genitalia in boys, hyperandrogenism in girls

P450 side-chaincleavage deficiency(CYP11A1 mutations)

XY sex reversal

P450 oxidoreductasedeficiency

Skeletal malformations, abnormal genitalia

Congenital lipoidadrenal hyperplasia(StAR mutations)

XY sex reversal

Adrenal hypoplasiacongenita

X-linked NROB1, Xp21 deletion (with Duchenne’s muscular deficiency), SF-1 mutations (XY sexreversal), IMAGe syndrome

ACTH insensitivitysyndromes

Type 1: ACTH receptor, melanocortin 2 receptor gene MC2RType 2: MRAPFamilial glucocorticoid deficiency (MCM4, NNT, TXNRD2)TripleA (Allgrove’s) syndrome, achalasia, Addison’s disease, alacrima, AAAS gene mutation

Drug-induced Adrenal enzyme inhibitors: mitotane, ketoconazole, metyrapone, etomidate, aminoglutethimide,drugs that may accelerate cortisol metabolism and induce adrenal insufficiency

T4 also accelerates cortisol metabolism (at least in part through stimulation of 11�-HSD2)CTLA-4 inhibitors may enhance autoimmunity and cause PAI

Other metabolic disorders Mitochondrial disease (rare)Adrenoleukodystrophy in malesWolman’s disease

Abbreviations: APECED, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy; CMV, cytomegalovirus; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; CYP, cytochrome P; HSD, hydroxysteroid dehydrogenase; 11�-HSD2, 11�-hydroxysteroid dehydrogenase type 2;IMAGe, intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenital, genital abnormalities; MC2R, melanocortin 2receptor gene; MCM4, minichromosome maintenance-deficient 4; MRAP, melanocortin receptor accessory protein; NNT, nicotinamide nucleotidetranshydrogenase; StAR, steroidogenic acute regulatory protein; TXNRD2, thioredoxin reductase 2. [Derived from E. Charmandari E, et al: Adrenalinsufficiency. Lancet. 2014;383:2152–2167 (164), with permission. © Elsevier.]

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immunoassays use different detection antibodies that pro-vide results that may demonstrate significant bias betweenmethods. For example, the low reference limit for cortisol30 minutes after the corticotropin stimulation ranges from418 to 574 nmol/L (15.2–20.8 �g/dL) (43, 44). The actualcutpoint used in clinical practice to make the diagnosisshould be based on assay-specific normative data. Thelaboratory providing the result should be able to providethe performance bias of the cortisol method in use. Tra-ditionally, a peak cortisol concentration after acute stim-ulation with corticotropin exceeding 500 nmol/L (18 �g/dL) is accepted as evidence for sufficient adrenocorticalresponsiveness (32, 45–47). It is important to considerother factors that will affect interpretation of the result,in particular the factors that alter protein binding ofcortisol to CBG (48) and to a lesser extent albumin (49).Importantly, the use of the estrogen-containing oralcontraceptives will result in higher CBG with a corre-sponding rise in cortisol (43, 44). Patients with diseasessuch as nephrotic syndrome (43) and liver disease (50)as well as those who are in the immediate postoperativeperiod (51) or who require intensive care (52) may havelower CBG and albumin and hence, lower cortisolmeasurements.

2.2 We suggest the low-dose (1 �g) corticotropin testfor diagnosis of PAI only when the substance itself is inshort supply. (2�QQEE)

EvidenceAlthough the stimulated increase of cortisol after 30 or

60 minutes in healthy individuals is comparable for bothlow-dose (1 �g) and high-dose (250 �g) corticotropintests, resulting in a lower cutoff threshold (mean �2SD) of500 nmol/L (18 �g/dL) (46, 53), the stimulated serumcortisol concentrations differ considerably at 60 minutesbetween both conditions, with a further rise in the high-dose test and a decrease of cortisol in the low-dose test (54,55). Cosyntropin-stimulated cortisol levels are slightlyhigher at 60 vs 30 minutes; however, the 30-minute timepoint has been validated against the insulin tolerance test(56). Further research is needed to determine whether thetraditionally used 60-minute cortisol level is in fact morespecific for diagnosis of adrenal insufficiency. Althoughthe low-dose and high-dose corticotropin stimulation testsyield comparable results in the diagnostic workup of PAIand the low-dose test adds no further sensitivity or spec-ificity over the high-dose test (47, 57), evidence has beenpresented that the low-dose corticotropin stimulation test

Figure 1. Algorithm for the diagnostic approach to the patient with PAI. The most common causes of PAI are autoimmune destruction of theadrenal cortex in adults and CAH in children. These etiologies can be screened for using 21-hydroxylase antibodies and a baseline serum 17-hydroxyprogesterone level. Males with negative 21-hydroxylase antibodies should be tested for adrenoleukodystrophy with plasma VLCFAs. Ifthese diagnoses are excluded, a CT scan of the adrenals may reveal evidence of adrenal infiltrative processes or metastases. The individual’s clinicalpicture and family history may render some steps in the algorithm redundant or suggest specific genetic syndromes. The latter includes subtypes ofautoimmune polyglandular syndromes or specific rare genetic disorders where adrenal failure is part of a broader phenotype. A list of differentialdiagnoses is provided in Table 2. AHC, adrenal hypoplasia congenita; AI, adrenal insufficiency; VLCFA, very long chain fatty acid. a 17-OH-progesterone �1000 ng/dL is diagnostic for 21-OH deficiency (14). b VLCFA should be measured in the initial evaluation of preadolescent boys.[Adapted from E. S. Husebye, et al: Consensus statement on the diagnosis, treatment and follow-up of patients with primary adrenal insufficiency.J Intern Med. 2014;275:104–115 (181), with permission. © John Wiley & Sons, Inc.]

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provides higher sensitivity in the diagnosis of secondaryadrenal insufficiency than the high-dose test (18, 29). Al-though similar arguments for the utility of the low-dosetest have been proposed for other special diagnostic chal-lenges such as the detection of adrenal insufficiency incritically ill patients (critical illness-related corticosteroidinsufficiency), more evidence is needed to support such aformal recommendation (47, 58, 59).

Thus, for practical reasons, the low-dose test may beapplicable to situations when corticotropin is in short sup-ply or for other structural or economic reasons. Althoughdilution and storage of the lower concentrated solutionmay be regarded as critical, it is worth noting that dilutedtetracosactide (in 0.9% saline at 1 �g/mL) has been re-ported to be stable at 2–8°C for up to 60 days (60).

Technical remarksThe diagnostic preparation of cosyntropin is supplied

in ampules containing 250 �g, and injection of thisamount yields a very high stimulus for the adrenal cortex,resulting in reproducible and valid test results. This test isalso usually well tolerated by the patient. The low-dose(1 �g) corticotropin test requires dilution of the suppliedcorticotropin to the required dose, which can introducedosing errors and sources of contamination into the diag-nostic procedure.

2.3 If a corticotropin stimulation test is not feasible, wesuggest using a morning cortisol �140 nmol/L (5 �g/dL)in combination with ACTH as a preliminary test sugges-tive of adrenal insufficiency (until confirmatory testingwith corticotropin stimulation is available). (2�QEEE)

EvidenceThis suggestion is only applicable in acute situations

when waiting for the corticotropin stimulation would un-necessarily delay appropriate therapy. It should not beused for community-based screening for PAI. In the ab-sence of exogenous glucocorticoids, a cutoff threshold forbasal cortisol concentrations of �140 nmol/L (5 �g/dL)drawn in the morning (6 to 10 AM) is suggestive of adrenalinsufficiency (18). Unfortunately, most of the primary re-ports detailing this cutoff value are not based on subjectswith PAI (23, 24, 61–64). In addition, the cortisol of 140nmol/L (5 �g/dL) is typically below or near the lower limitof the range of normal subjects (collected between 6 and10 AM) in reference populations for assays in contempo-rary clinical laboratories: 113–131 nmol/L (4.1–4.7 �g/dL) (44, 65). As mentioned in Section 2.1, the variationbetween different cortisol methods will affect the actualcut-point used in clinical practice, and this should be de-termined in conjunction with the laboratory providing theassay.

It shouldbenotedthat thechoiceofwhatmorningcortisolconcentration to utilize to rule out adrenal insufficiency(100% sensitivity) is controversial, with studies arguing lev-els from�285nmol/L (10.3�g/dL) (23) to�480nmol/L (17�g/dL) (62). There is no evidence to support the use of ran-dom cortisol to rule out adrenal insufficiency.

2.4 We recommend measurement of plasma ACTH toestablish PAI. The sample can be obtained at the same timeas the baseline sample in the corticotropin test or paired withthe morning cortisol sample. In patients with confirmed cor-tisol deficiency, a plasma ACTH �2-fold the upper limit ofthe reference range is consistent with PAI. (1�QQQE)

EvidenceA plasma ACTH concentration exceeding 300 ng/L (66

pmol/L) provides maximum stimulation of glucocorticoidsynthesis (19), and accordingly, a low cortisol concentra-tion (�140 nmol/L [�5 �g/dL]) found in combinationwith an elevated concentration of ACTH indicates the in-ability of the adrenal cortex to respond to ACTH stimu-lation and is highly predictive for PAI (19, 20, 66, 67). Anelevated ACTH concentration in the presence of a cortisolin the normal range can be the first sign of early-stage PAI(68). The challenge with setting a specific cut-point forACTH levels suggesting PAI is highly influenced by ana-lytical bias demonstrated in ACTH assays (69, 70). Onlytwo studies have reported the ACTH range for PAI atdiagnosis with a control reference population, and in thesestudies the ACTH was typically grossly elevated in PAI.Thus, we have recommended the 2 � the upper limit of thereference interval, but in some cases of PAI it would beonly above the quoted reference interval but not �2 � theupper limit of the reference interval (19, 20).

2.5 We recommend the simultaneous measurement ofplasma renin and aldosterone in PAI to determine the pres-ence of mineralocorticoid deficiency. (1�QQQE)

EvidenceDetermination of renin and aldosterone can be of di-

agnostic value because in the early phase of evolving PAI,mineralocorticoid deficiency may predominate (71) andmay be the only sign (72). Thus, an elevated plasma reninactivity or concentration in combination with an (inap-propriately) normal or low serum aldosterone concentra-tion is suggestive of PAI (38, 71–74). Both renin and al-dosterone measurements have a number of importantchallenges from the laboratory perspective and should beinterpreted based on the reference intervals provided onthe report (75). However, in some cases of PAI, eg, infamilial glucocorticoid deficiency or patients with milder

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mutations causing CAH, adrenal mineralocorticoid pro-duction may not be compromised.

2.6 We suggest that the etiology of PAI should be de-termined in all patients with confirmed disease. (For di-agnostic workup, see Table 2 and Figure 1) (Ungraded bestpractice recommendation)

EvidenceWhen PAI has been confirmed at the hormonal level, it

is important for therapeutic reasons to identify the causeof the disease (Figure 1 and Table 2). Autoimmune adre-nalitis is the most common cause, accounting for the vastmajority of adult cases, and screening for specific auto-antibodies against CYP21A2 and for other associated au-toimmune diseases is important, keeping in mind that thelaboratory tests for the autoantibodies are not standard-ized and are subject to wide between-method variation (7,76–79). Finding CYP21A2 autoantibodies, which can bepresent several years before biochemical and clinical evi-dence of PAI, strengthens the suspicion that overt PAI islikely to develop. Following CYP21A2 autoantibody-pos-itive individuals revealed that about 30% progressed toovert PAI during a 5-year follow-up (72).

In children with autoimmune PAI, autoimmune polyen-docrine syndrome (APS)-1 should be considered with eval-uation for hypoparathyroidism and mucocutaneous candi-diasis and measurement of antibodies to interferon � or �

that have a high diagnostic sensitivity and specificity (80).Young males and males without autoantibodies should bescreened for adrenoleukodystrophy by measuring very-longchain fatty acids (81, 82). Adrenal insufficiency may be theonly presenting sign of adrenoleukodystrophy, which mostoften occurs in boys between 2 and 10 years of age. InCYP21A2 autoantibody-negative individuals with PAI ofunknown etiology, we suggest a computer tomography (CT)scan of the adrenals to identify infectious diseases like tuber-culosis and tumors. CT scanning for these conditions is gen-erally not specific for the infiltrative disorder, and not allpatients with infiltrative adrenal conditions such as tubercu-losis causing PAI have enlarged adrenals. Genetic diseases inwhich ACTH is chronically elevated result in bilateral adre-nal enlargement and should be considered in select cases. Avariety of rare conditions may require additional diagnosticmeasures like serological or microbiological testing (12, 83).The nonautoimmune cases of PAI are more frequently seenamong children and the elderly. CAH due to 21-hydroxylasedeficiency is the most common cause of adrenal insufficiencyin infancy (14).

3.0 Treatment of primary adrenal insufficiency inadults

Glucocorticoid replacement regimen3.1 We recommend glucocorticoid therapy in all pa-

tients with confirmed PAI. (1�QQQQ)

3.2 We suggest using hydrocortisone (15–25 mg) orcortisone acetate (20–35 mg) in two or three divided oraldoses per day; the highest dose should be given in themorning at awakening, the next either in the early after-noon (2 h after lunch; two-dose regimen) or at lunch andafternoon (three-dose regimen). Higher frequency regi-mens and size-based dosing may be beneficial in individualcases. (2�QQEE)

3.3 As an alternative to hydrocortisone, we suggest us-ing prednisolone (3–5 mg/d), administered orally once ortwice daily, especially in patients with reduced compli-ance. (2�QEEE)

3.4 We suggest against using dexamethasone for thetreatment of PAI because of risk of Cushingoid side effectsdue to difficulties in dose titration. (2�QQEE)

3.5 We suggest monitoring glucocorticoid replacementusing clinical assessment including body weight, posturalblood pressure, energy levels, signs of frank glucocorticoidexcess. (2�QQQE)

3.6 We suggest against hormonal monitoring of gluco-corticoid replacement and to adjust treatment only basedon clinical response. (2�QQQE)

EvidenceGlucocorticoids are secreted in a pulsatile and circadian

rhythm, with the highest peak in the morning, with lowlevels in the evening, reaching a nadir around midnight(84). Mean cortisol production rates are influenced by ageand body composition and have been reported to be about5–8 mg/m2/d (85–88), which is equivalent to an oral re-placement with 15–25 mg/d (with a tendency toward thelower margin to avoid overtreatment) of hydrocortisoneor 20–35 mg of cortisone acetate in adults. In most in-dustrialized countries, hydrocortisone is the preferredpharmacological replacement agent, but cortisone acetateis also in widespread use. In a number of countries, onlyprednisolone is available.

Hydrocortisone and prednisolone are active glucocor-ticoids, whereas cortisone acetate and prednisone requireactivation via hepatic 11�-hydroxysteroid dehydrogenasetype 1 activity before exerting biological activity. Replace-ment with inactive precursor glucocorticoids may resultin broader interindividual variability of pharmacoki-netic parameters (89), but this has not been studiedsystematically.

Because of the short plasma half-life of hydrocortisone(approximately 90 min) (90), multiple dosing is recom-mended to mimic physiological conditions. The first andlargest dose is suggested to be given upon awakening, thesecond dose after lunch, and, in case of a three-dose reg-imen, the last and smallest dose not later than 4–6 hoursbefore bedtime. The rationale for this regimen is to try to

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mimic the circadian rhythm and also to avoid high dosesin the evening, which may compromise sleep and insulinsensitivity (91, 92).

Only small studies have compared dosing regimens.Using the fluctuating normal range of cortisol throughoutthe 24-hour day as a goal, Peacey et al (93) and Howlett(94) independently recommended 10 mg hydrocortisoneon awakening, 5 mg at lunchtime, and 5 mg in the earlyevening. Some patients appear to require higher glucocor-ticoid doses, but these must be used with caution. In single-dose morning studies of adrenal insufficiency patients, hy-drocortisone adjusted by body surface area (5.5 mg/m2) orby weight (0.12 mg/kg) produced integrated cortisol levelsover 6 hours reliably within the healthy control 95% con-fidence intervals, whereas fixed dosing at 10 mg hydro-cortisone did not (95). Hence, dose adjustment by weightor body surface area may produce more physiological cor-tisol levels in PAI patients than fixed dose regimens. Lau-reti et al (96) and Barbetta et al (97) found that thrice-dailycortisone acetate lowered ACTH levels and gave 24-hourcortisol curves more similar to the endogenous cortisolrhythm compared with a two-dose regimen. One double-blind, randomized, crossover study evaluating two-dosevs four-dose hydrocortisone treatments (98) concludedthat cortisol pharmacokinetics were more physiologicalon the four-dose regimen; surprisingly, participating pa-tients preferred this regimen. Conversely, Alonso et al (99)found that HRQoL scores were similar and on some pa-rameters worse on thrice-daily compared with twice-dailyhydrocortisone. Taken together, because few and mostlyunderpowered short-term studies have been performed, itis difficult to make strong global recommendations onthese different regimens. Based on prevailing evidence andclinical experience, three or four daily doses give morephysiological cortisol profiles that may be beneficial tocounter long-term complications of glucocorticoid re-placement. Weight-adjusted dosing will increase thechance of obtaining a cortisol value within the referencerange. However, outcome studies confirming this hypoth-esis are lacking, and less-frequent dosing may be associ-ated with better compliance (100).

Rigorous pharmacokinetic studies have only comparedhydrocortisone vs cortisone acetate in adrenal insuffi-ciency. The absorption curve of cortisone acetate is lesssteep and is delayed compared with that of hydrocortisone(89, 101), which might be favorable considering the shorthalf-life of hydrocortisone. Although clinical experiencesupports the recommendation of both drugs, individualpatients may prefer one over the other.

When PAI patients fail to recover in terms of HRQoLand working capacity or have difficulty adhering to a mul-tiple-dose regimen, prednisolone, 3–5 mg/d administered

in one or two doses, can be prescribed. Retrospective stud-ies of patients taking higher doses of glucocorticoids insome cases, including prednisolone or dexamethasone,appear to show a tendency to adverse metabolic conse-quences including weight gain, dyslipidemia, and diabetesmellitus (102). However, prospective studies comparingthe safety and efficacy of prednisolone and hydrocortisoneover time are not available. It is the experience of somephysicians that higher doses of prednisolone achieve goodresults is some patients. Dexamethasone should beavoided because Cushingoid side effects frequently appear(103). Alternatively, a newly marketed dual-release hy-drocortisone preparation can be administered once daily(104). However, whereas this dual-release hydrocortisonepreparation was shown to slightly reduce blood pressureand HbA1c (104), such results may not always be desir-able in patients with PAI. Moreover, such variability canreflect differences in glucocorticoid bioavailability be-tween the dual-release formulation and the hydrocorti-sone control dosing regimen. Other slow-release prepara-tions of hydrocortisone are in clinical development (seePerspectives and Demand for Future Research below).Additional, preferably double-blind, studies are neededto fully evaluate possible advantages of these prepara-tions over current hydrocortisone and cortisone acetateregimens.

Monitoring glucocorticoid replacement relies primar-ily on clinical assessment. Symptoms and signs of over-replacement are weight gain, insomnia, and peripheraledema. Insufficient dosing is characterized by nausea,poor appetite, weight loss, lethargy, and hyperpigmenta-tion. Detailed questioning about the patient’s daily habits,working patterns (eg, shift work), general feelings of en-ergy, mental concentration, daytime somnolence, and dipsin energy can help fine-tune when tablets should be taken,how often, and at what dose. Compliance and use of extradoses should be mapped. In cases when malabsorption issuspected, serum or salivary cortisol day curve monitoringmay be useful to guide dosing.

Measurement of plasma ACTH to guide glucocorticoidreplacement doses is not recommended because patientswho receive appropriate replacement often have elevatedACTH levels, due to disturbance of the normal closerelationship between ACTH and cortisol secretion andnegative feedback. Use of ACTH levels to adjust glu-cocorticoid replacement is clinically known to lead toover-replacement.

Mineralocorticoid replacement in PAI3.7 We recommend that all patients with confirmed

aldosterone deficiency receive mineralocorticoid replace-

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ment with fludrocortisone (starting dose, 50–100 �g inadults) and not restrict their salt intake. (1�QQQQ)

3.8 We recommend monitoring mineralocorticoid re-placement primarily based on clinical assessment (saltcraving, postural hypotension, or edema), and blood elec-trolyte measurements. (1�QQQE)

3.9 In patients who develop hypertension while receiv-ing fludrocortisone, we suggest reducing the dose offludrocortisone. (2�QEEE)

3.10 If blood pressure remains uncontrolled, we sug-gest initiating antihypertensive treatment and continuingfludrocortisone. (2�QEEE)

EvidenceMineralocorticoids are vital for maintaining water and

electrolyte homeostasis, and thereby blood pressure. Thesynthetic mineralocorticoid 9�-fludrocortisone is used asreplacement therapy, but its use in PAI has not been stud-ied systematically. Fludrocortisone is routinely taken oncedaily in the morning, the rationale being that aldosteronelevel is highest at this time because it follows a circadianrhythm similar to cortisol (105). The fludrocortisone doseis related to individual fluid and electrolyte intake andlosses. A daily dose of 0.05–0.2 mg is usually sufficient inadults and adolescents with PAI. In newborns and chil-dren, mineralocorticoid sensitivity is lower, thereby usu-ally requiring higher fludrocortisone doses compared toadults (106). Temporary dose increments of 50–100% orincreased salt intake can be recommended in a hot climateand conditions that promote excessive sweating. In addi-tion, the patients should be advised not to restrict their saltintake. Patients on prednisolone may require more fludro-cortisone than those on hydrocortisone because pred-nisolone has less mineralocorticoid activity. Dexametha-sone does not exert any mineralocorticoid activity.

Mineralocorticoid replacement is assessed clinically byinquiring about salt craving or light-headedness, measur-ing blood pressure in the sitting and standing position, andidentifying the presence of peripheral edema, although thelatter is of low sensitivity. General well-being, electrolyteswithin the normal range, and normal blood pressure with-out evidence of postural hypotension indicate adequatemineralocorticoid replacement. Furthermore, plasmarenin activity in the upper reference range has been foundto be a useful marker for a correct mineralocorticoid dose(38, 107, 108). Licorice and grapefruit juice potentiate themineralocorticoid effect of hydrocortisone and should beavoided (109). Phenytoin has been reported to increasefludrocortisone metabolism, leading to a need for higherreplacement (110).

Primary hypertension may also be present in PAI (111).Assessment of the hypertensive PAI patient should involve

an evaluation of not only the fludrocortisone dose but alsothe glucocorticoid dose because overtreatment with eitherpreparation can lead to hypertension. If hypertensionprevails after adjustment and the patient is euvolemic,angiotensin II receptor blockers or angiotensin-convert-ing enzyme blockers may be used to counter the vaso-constrictive effects of elevated angiotensin II (112). Sec-ond-line treatment can include a dihydropyridinecalcium blocker. Diuretics should be avoided. Aldoste-rone receptor blockers such as spironolactone andeplerenone are contraindicated.

Dehydroepiandrosterone replacement3.11 We suggest a trial of DHEA replacement in women

with PAI and low libido, depressive symptoms, and/or lowenergy levels despite otherwise optimized glucocorticoidand mineralocorticoid replacement. (2�QQEE)

3.12 We suggest an initial period of 6 months of DHEAreplacement. If the patient does not report a sustained,beneficial effect of replacement after 6 months, the DHEAshould be discontinued. (2�QQEE)

3.13 We suggest monitoring DHEA replacement bymeasuring morning serum DHEAS levels (aiming at themidnormal range) before the intake of the daily DHEAreplacement dose. (2�QQEE)

EvidenceIn women, adrenal production of the androgen precur-

sors DHEA and androstenedione is a major source of an-drogen production. Consequently, adrenal insufficiency isfrequently associated with androgen deficiency in femalepatients. Serum DHEAS concentrations physiologicallypeak between ages 20 and 30 years, followed by a gradualdecline that is independent of menopause (113). The ad-renal androgen precursor DHEA is activated to sex ste-roids in a wide variety of peripheral tissues and in thegonads, but it has also been shown to have neurosteroidalproperties with potential antidepressive action in thebrain. DHEA replacement in PAI with a single oral dosehas been shown to restore circulating levels of androgenprecursors and androgens back to the normal range (3,114). In addition, some (but not all) studies have shownthat DHEA replacement in adrenal insufficiency may im-prove HRQoL and mood, with reduced depression andanxiety scores (114–116). A systematic review and meta-analysis of randomized placebo controls of DHEA treat-ment have not shown any substantial clinical benefit, sug-gesting that the current evidence is insufficient to supportroutine use of DHEA in women with adrenal insufficiency(117).

A number of studies have documented positive effectson libido, and DHEA replacement restores pubarche in

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adolescent adrenal insufficiency patients (118). Studies onlong-term outcomes of chronic DHEA supplementation inwomen with PAI are lacking and are unlikely to be avail-able soon due to a lack of commercial interest and theready availability of DHEA over the counter or throughinternet orders.

DHEA replacement (25–50 mg as a single oral dose inthe morning) may be considered in premenopausal womenwith PAI and in the presence of reduced or absent libido,depression, anxiety, and reduced energy levels despite oth-erwise optimized glucocorticoid and mineralocorticoid re-placement. In addition to looking at clinical efficacy andpotential side effects, the appropriateness of the DHEAdose during treatment should be monitored by a morningblood sample for serum DHEAS, before taking the nextdose of DHEA, aiming at the midrange of a premeno-pausal female reference cohort.

Treatment during pregnancy3.14 We suggest that pregnant patients with PAI be

monitored for clinical symptoms and signs of glucocorti-coid over- and under-replacement (eg, normal weightgain, fatigue, postural hypotension or hypertension, hy-perglycemia), with at least one review per trimester. (Un-graded best practice statement)

3.15 We suggest that, based on the individual clinicalcourse, an increase in hydrocortisone dose should be im-plemented, in particular during the third trimester. (Un-graded best practice statement)

3.16 In pregnant women with PAI, we suggest usinghydrocortisone over cortisone acetate, prednisolone, orprednisone (2�QQEE) and recommend against usingdexamethasone because it is not inactivated in the pla-centa. (1�QQEE)

3.17 We recommend hydrocortisone stress dosing dur-ing the active phase of labor, similar to that used in majorsurgical stress. (1�QQEE)

EvidenceDuring normal pregnancy, circulating cortisol concen-

trations are increased 2- to 3-fold, with a continuous in-crease from the first trimester onward due to increases inCBG levels (40, 42). From week 22 of gestation onward,free cortisol levels also increase significantly, with a fur-ther rise immediately preterm due to a fall in CBG (42,119); cortisol levels return to normal after delivery (40).Adrenal crisis due to insufficient glucocorticoid dose ad-justment during pregnancy has been reported (120). Al-though little evidence exists on the exact regimen of op-timized glucocorticoid replacement in pregnancy, onecommon approach is to increase hydrocortisone dose by20–40% from the 24th week onward to reflect the phys-

iological increase in free cortisol. Glucocorticoid prepa-rations that can be used in pregnancy are hydrocortisone,cortisone acetate, prednisolone, and prednisone; dexa-methasone is usually contraindicated because it is not in-activated by placental 11�-hydroxysteroid dehydroge-nase type 2 and thus crosses the placenta to the fetus.

The diagnosis of new-onset adrenal insufficiency inpregnancy is challenging because symptoms are nonspe-cific and often are not different from those commonlypresent in pregnancy itself, such as fatigue, nausea, andvomiting. The cosyntropin stimulation test is the test ofchoice in pregnant women if adrenal insufficiency is sus-pected. In a small cohort of healthy pregnant women, thepeak total cortisol response after ACTH injection was sig-nificantly higher in comparison to the nonpregnant state(median, 1000 nmol/L [37 �g/dL]) in the second and thirdtrimesters, whereas their responses returned to prepreg-nancy levels during the postpartum period (median, 700nmol/L [26 �g/dL]) (41). Thus, it has been suggested to usehigher diagnostic cortisol cutoffs of 700 nmol/L (25 �g/dL), 800 nmol/L (29 �g/dL), and 900 nmol/L (32 �g/dL)for the first, second, and third trimesters, respectively (40).

Mineralocorticoid requirements during pregnancy aremore difficult to assess, again due to nonspecific symp-toms overlapping with those observed in physiologicalpregnancy, such as edema or postural hypotension. So-dium and potassium can be monitored in blood and urine,whereas plasma renin physiologically increases duringpregnancy and therefore cannot be used for monitoringpurposes. There is some evidence that aldosterone in-creases during normal pregnancy (41) and serum proges-terone steadily increases throughout pregnancy, exertingsome anti-mineralocorticoid effect; hence, fludrocorti-sone dose adjustments are sometimes required (121).However, in most cases this will be covered by the increasein glucocorticoid replacement dose in the later stages ofpregnancy.

A hydrocortisone dose equivalent to that used for ma-jor surgical stress should be initiated at the onset of activelabor (cervix dilation � 4 cm and/or contractions every 5min for the last hour) with a bolus injection of 100 mghydrocortisone iv followed by continuous infusion of 200mg hydrocortisone/24 hours (40, 122). After delivery, hy-drocortisone can be quickly tapered back to prepregnancydoses.

Treatment and monitoring during childhood3.18 In children with PAI, we suggest treatment with

hydrocortisone in three or four divided doses (total start-ing daily dose of 8 mg/m2 body surface area) over othertypes of glucocorticoid replacement therapies, with dosesadjusted according to individual need. (2�QQEE)

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3.19 In children with PAI, we suggest avoiding syn-thetic, long-acting glucocorticoids (eg, prednisolone,dexamethasone). (2�QQEE)

3.20 We suggest monitoring glucocorticoid replace-ment by clinical assessment, including growth velocity,body weight, blood pressure, and energy levels. (Ungradedbest practice statement)

3.21 In children with PAI and confirmed aldosteronedeficiency, we recommend treatment with fludrocortisone(starting dosage, 100 �g/d). For infants, we recommendsodium chloride supplements in the newborn period andup to the age of 12 months. (1�QQEE)

EvidenceThere are no published randomized, controlled trials of

various treatment regimens for PAI in children. Treatmentin children is aimed at controlling the symptoms of adrenalinsufficiency with a dose that allows adequate growth andpubertal development. No data are available to comparethe long-term effects of various formulations of glucocor-ticoid. However, hydrocortisone has a short half-life andis easier to titrate in children. This minimizes the adverseside effects compared with the more potent longer-actingglucocorticoids. Most data available on the treatment ofchildren with PAI are in children with adrenal insuffi-ciency due to CAH. However, patients with adrenal in-sufficiency due to CAH have the additional risk of hy-perandrogenism with undertreatment resulting in the needfor higher glucocorticoid therapy; this risk is not presentin PAI due to other causes. Estimates of normal cortisolsecretion rate can be used to determine an initial hydro-cortisone dose (85). The daily dose is usually divided intotwo or preferably three doses, with a typical daily dose ofabout 8 mg/m2. Cortisone acetate may be used instead ofhydrocortisone; however, caution should be used because11�-hydroxysteroid dehydrogenase type 1 activity is vari-able in childhood (123), and it is uncertain whether thehydrocortisone dose equivalency used in adults applies inchildren.

Overtreatment must be avoided, and daily dose shouldbe adjusted depending on clinical status and growth. Theglucocorticoid dose will need to be increased to accountfor a child’s increasing body surface area. Excessive weightgain with decreased height velocity or other symptoms orsigns of Cushing syndrome indicate excessive glucocorti-coid replacement. In patients with CAH, glucocorticoiddosages exceeding 20 mg/m2/d in infants and 15 to 17mg/m2/d in adolescents have been shown to result in lossof height and shorter adult stature (124, 125). Growthsuppression at lower dosages is also possible because dos-ages above 8 mg/m2/d may exceed the physiological range;thus, close follow-up of growth and weight velocities and

general clinical well-being are most important for doseadjustments. Measurement of plasma ACTH is typicallyabove the normal range and is not useful for routine mon-itoring. Inadequate weight gain, fatigue, anorexia, andhyperpigmentation suggest the need for increased medi-cation dose.

Children with PAI require mineralocorticoid replace-ment with fludrocortisone. A typical daily dose is 100 �g.The mineralocorticoid dose does not require adjustmentby body surface area and often remains the same through-out life. However, infants, especially in the first 6 monthsof life, require sodium chloride supplementation of 1 to 2g/d (17 to 34 mmol/d), divided in several feedings due tomineralocorticoid resistance in the immature infant kid-ney and the relatively low sodium content of formula andbreast milk (14).

Signs and symptoms of inadequate mineralocorticoidreplacement include poor weight gain, salt craving, dehy-dration, hyponatremia with hyperkalemia, and elevatedplasma renin activity or concentration. Excessive miner-alocorticoid replacement results in hypertension and sup-pressed plasma renin. Monitoring of blood pressureshould be performed routinely. Assessment of plasmarenin should be done periodically in response to changesin clinical status or if compliance is in question.

Infants require frequent assessment and should be eval-uated at a minimum every 3 to 4 months to assess growth,blood pressure, and general well-being. Over the firstmonths of life, sensitivity to mineralocorticoid increases;thus, it is especially important to monitor blood pressureduring the first year of life.

4.0 Management and prevention of adrenal crisisin patients with PAI

4.1 We recommend that patients with suspected adre-nal crisis should be treated with an immediate parenteralinjection of 100 mg (50 mg/m2 for children) hydrocorti-sone, followed by appropriate fluid resuscitation and 200mg (50–100 mg/m2 for children) of hydrocortisone/24hours (via continuous iv therapy or 6 hourly injection);age- and body surface-appropriate dosing is required inchildren (Table 3). (1�QQQE)

4.2 If hydrocortisone is unavailable, we suggest pred-nisolone as an alternative. Dexamethasone is the least-preferred alternative and should only be given if no otherglucocorticoid is available. (2�QQEE)

EvidencePatients with PAI are at risk of life-threatening adrenal

crises. Adrenal crisis occurs when the adrenal glands can-not produce sufficient cortisol in response to an increasedneed. The major clinical features of adrenal crisis are hy-

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potension and volume depletion. Combined glucocorti-coid and mineralocorticoid deficiency results in urinarysodium loss, hyponatremia, hyperkalemia, increased se-rum urea, and hypoglycemia; the latter is most relevant inchildren, but rarely occurs in adults.

Under-dosing of glucocorticoids in an adrenal crisis ispotentially hazardous. However, there are no systematicdose-response-studies, and therefore the glucocorticoiddoses recommended for the treatment of adrenal crisis arelargely on an empiric basis.

Adrenal crisis in patients with known PAI is best pre-vented by patient education and increasing the glucocor-ticoid dosage in situations of stressors known to increasecortisol requirements (126).

In a retrospective analysis of 444 patients with adrenalinsufficiency, the frequency of adrenal crises in adult pa-tients with PAI was 6.6 adrenal crises/100 patient years(120). The main precipitating factors were gastrointesti-nal diseases (32.6%) and other infectious disease (24.3%).Similarly, a postal survey of over 1000 patients with PAIfrom four countries (United Kingdom, Canada, Australia,New Zealand) found 8% of patients experienced an ad-renal crisis annually, and gastrointestinal infection andflu-like illnesses were the two most common triggers(127). In a first prospective study comprising 768 patientyears, 8.3 crises/100 patient years were reported (128).

Based on these data, about one in 12 patients will expe-rience a life-threatening crisis in the coming year. Further-more, in this first prospective study, a mortality rate fromcrisis of 0.5/100 patient years was reported. Adrenal crisisis alsoacommonoccurrence inpatientswithCAH,althoughdetailed data are only available from pediatric patients. In across-sectional questionnaire-based study of 122 patientswith PAI due to classic CAH, the reported frequency of ad-renal crises was 5.8 adrenal crises/100 patient years (4.9 ad-renal crises/100 patient years after correction for a neonatalsalt-wasting crisis) (129). An age-related pattern emerged;respiratory infections were the main trigger in early child-hood, whereas gastrointestinal infections were the maincause at older ages. The median time from recognition of thefirst symptoms to overt adrenal crisis was 1 day.

The addition of co-medication that alters cortisol clear-ance could also trigger an adrenal crisis, and considerationof a glucocorticoid dose increase and re-evaluation shouldoccur. Initiation of T4 replacement may induce adrenalcrisis due to increased cortisol metabolism (130). Medi-cations that induce the drug-metabolizing enzymeCYP3A4 (eg, carbamazepine, mitotane, St John’s wort)also increase cortisol clearance, necessitating a higher re-placement dose (131). Similarly, glucocorticoid replace-ment with dexamethasone without concurrent fludrocor-tisone can trigger anadrenal crisis becausedexamethasone

Table 3. Management of PAI in Specific Situations

Condition Suggested Action

Home management of illnesswith fever

Hydrocortisone replacement doses doubled (�38°C) or tripled (�39°C) until recovery (usually2 to 3 d); increased consumption of electrolyte-containing fluids as tolerated

Unable to tolerate oralmedication due togastroenteritis or trauma

Adults, im or sc hydrocortisone 100 mg; children, im hydrocortisone 50 mg/m2 or estimate;infants, 25 mg; school-age children, 50 mg; adolescents, 100 mg

Minor to moderate surgicalstress

Hydrocortisone, 25–75 mg/24 h (usually 1 to 2 d)Children, im hydrocortisone 50 mg/m2 or hydrocortisone replacement doses doubled or tripled

Major surgery with generalanesthesia, trauma, delivery,or disease that requiresintensive care

Hydrocortisone, 100 mg per iv injection followed by continuous iv infusion of 200 mghydrocortisone/24h (alternatively 50 mg every 6 h iv or im)

Children, hydrocortisone 50 mg/m2 iv followed by hydrocortisone 50–100 mg/m2/d divided q6 h

Weight-appropriate continuous iv fluids with 5% dextrose and 0.2 or 0.45% NaClRapid tapering and switch to oral regimen depending on clinical state

Acute adrenal crisis Rapid infusion of 1000 mL isotonic saline within the first hour or 5% glucose in isotonic saline,followed by continuous iv isotonic saline guided by individual patient needs

Hydrocortisone 100 mg iv immediately followed by hydrocortisone 200 mg/d as a continuousinfusion for 24 h, reduced to hydrocortisone 100 mg/d the following day

Children, rapid bolus of normal saline (0.9%) 20 mL/kg. Can repeat up to a total of 60 mL/kgwithin 1 h for shock.

Children, hydrocortisone 50–100 mg/m2 bolus followed by hydrocortisone 50–100 mg/m2/ddivided q 6 h

For hypoglycemia: dextrose 0.5–1 g/kg of dextrose or 2–4 mL/kg of D25W (maximum singledose 25 g) infused slowly at rate of 2 to 3 mL/min. Alternatively, 5–10 mL/kg of D10W forchildren �12 y old

Cardiac monitoring: Rapid tapering and switch to oral regimen depending on clinical state

Abbreviation: D10W, 10% dextrose solution; D25W, 25% dextrose solution. [Adapted from B. Allolio: Extensive expertise in endocrinology:adrenal crisis. Eur J Endocrinol. 2015;172:R115–R124 (126), with permission. © Endocrine Society.]

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has no mineralocorticoid activity. Based on traditionalstudies, 40 mg hydrocortisone are regarded as equivalentto 100 �g fludrocortisone (132–134), suggesting thathigher hydrocortisone doses are likely to provide replace-ment levels of mineralocorticoid activity.

High-intensity exercise for 20 minutes did not requireadditional hydrocortisone in CAH patients (135). Addi-tional hydrocortisone (5 to 10 mg) has been discussed forprolonged intensive fitness training in patients with PAI(136). However, there is no evidence for a generalrecommendation.

Values and preferencesThe proposed glucocorticoid regimen in the manage-

ment of adrenal crisis places a higher value on the preven-tion of underdosage than on reducing potential negativeeffects of short-term overdosage.

4.3 For the prevention of adrenal crisis, we suggest ad-justing glucocorticoid dose according to severity of illnessor magnitude of the stressor. (2�QQEE)

EvidenceStudies provide evidence for an endogenous increase in

cortisol during anesthesia, surgery, trauma, and criticalillness, with great interindividual variation (137–141).Enhanced glucocorticoid secretion in critical illness is con-sidered necessary to prevent defense mechanisms (eg, cy-tokine release) from overshooting with concomitant det-rimental toxicity (142, 143). There are no randomizedcontrolled studies evaluating glucocorticoid dose require-ments in patients with PAI during times of increased cor-tisol need. Glucocorticoid dose is typically based on theseverity and duration of the stressor. Traditionally, it isestimated that adults secrete 75–100 mg of cortisol/d inresponse to major surgery and 50 mg/d in response tominor surgery (144). The concept for giving these highdoses is not to mimic median values of normal subjectsduring surgery, but also to cover unexpected additionalneeds if complications occur. In addition, harm from thesedoses has not been shown, and direct studies indicatingthat lower doses are safe do not exist. In a review of peri-operative adrenal insufficiency in glucocorticoid-treatedpatients, cortisol secretion in the first 24 hours after sur-gery rarely exceeded 200 mg, and the secretion rate cor-related with the duration and extent of surgery (144).Lower doses of hydrocortisone (25–75 mg/24 h) for sur-gical stress have been advocated in patients with second-ary adrenal insufficiency (144, 145). This has not beenstudied in patients with PAI.

Reduced cortisol metabolism has been shown duringcritical illness (146). In a study of 158 intensive care unitpatients and 64 matched controls, total and free circulat-

ing cortisol levels were higher in the patients than in con-trols due to a reduction in cortisol clearance of more than50% and reduced inactivation of cortisol to cortisone. Theimplications of this reduced cortisol metabolism on glu-cocorticoid dosing during critical illness in patients withPAI has not been studied.

During febrile illness, the glucocorticoid dose is typi-cally taken orally at double or triple the usual daily dose,until recovery, usually of 2- to 3-day duration (Table 3). Ifthe patient is unable to tolerate oral medication due tovomiting or trauma, early parenteral (iv, im, or sc) injec-tion of 100 mg hydrocortisone is indicated. Mineralocor-ticoid replacement is not required if the hydrocortisonedose exceeds 50 mg/24 hours.

In a single-center, open-label, randomized, crossoverstudy of 12 patients with PAI, sc and im injection of hy-drocortisone had similar pharmacokinetics; however, scinjection required two single injections (vs one im injec-tion) and had slower time to reach a cortisol level �1000nmol/L (�36 �g/dL) (22 vs 11 min) (147). Subcutaneousself-injection was the route of administration preferred bythe patients, and the time delay in reaching peak cortisolconcentrations compares favorably with the time fromcontacting emergency help until eventual glucocorticoidadministration by health professionals (148). Rectal sup-positories (prednisolone 100 mg suppository) or enemas(prednisolone 20 mg/100 mL or hydrocortisone acetateenema 10%) have been successfully used but should not beused with diarrhea; they have not been extensively studiedand are not widely available (eg, not available in theUnited States).

Assumed values and preferencesThe proposed recommendation places a higher value

on prevention of adrenal crisis than on reducing the po-tential negative effect of short-term overtreatment.

Technical remarksSee Table 3 for details. Relevant conditions include sur-

gery, trauma, critical illness, and delivery.4.4 We suggest patient education concerning glucocor-

ticoid adjustments in stressful events and adrenal crisis-prevention strategies including parenteral self- or lay-ad-ministration of emergency glucocorticoids. (Ungradedbest practice statement)

4.5 We recommend that all patients should beequipped with a steroid emergency card and medicalalert identification to inform health personnel of theneed for increased glucocorticoid doses to avert or treatadrenal crisis and the need of immediate parenteral ste-roid treatment in the event of an emergency. (Ungradedbest practice statement)

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4.6 We recommend that every patient should beequipped with a glucocorticoid injection kit for emergencyuse and be educated on how to use it. (Ungraded bestpractice statement)

EvidenceMortality of patients with PAI was increased in some

(149, 150), but not all studies (7). However, in all thesereports, adrenal crisis was a significant cause of death.Thus, patient education for prevention of adrenal crisisand the use of emergency glucocorticoids is greatly needed(151). However, it has been shown that a high percentageof patients (46%) were not sufficiently skilled in steroidmanagement with physical stress (152). Thus, repeatededucation efforts should be part of outpatient visits. Alarge international survey found that approximately one-third of all medical emergencies in patients with PAI oc-curred outside the home. Only 12% of patients with anadrenal crisis in the previous year gave themselves an in-jection; over two-thirds relied on medical personnel fortheir first line of treatment (127). In a survey study of 26patients with Addison’s disease in the United Kingdom(153), only two patients could self-administer parenteralhydrocortisone, and 10 responders claimed never to havereceived injection teaching, although instruction was pro-vided as unit policy. In a survey of 60 caregivers of childrenwith CAH in the United States (154), 70% had receivedwritten guidelines regarding stress dosing, and half re-ceived injection teaching. In a survey of 254 patients withPAI in Germany, only 63% felt well informed about stressdosing (120).

Still, many patients meet physicians who are unawareof the need for immediate treatment of an adrenal crisis. Asteroid card can help overcome this hurdle. Recently, anew Swedish steroid card was introduced, with simpleinstructions in Swedish and English, and several Europeancountries are now introducing the same card with the na-tional language on one side and English on the other (155).A number of different steroid cards are in circulation (forexamples, see http://www.ese-hormones.org/professional/docs/ExistingEmergencyCards.pdf), issued by depart-ments of endocrinology, patient organizations, and thepharmaceutical industry. Such cards should be issued toall patients so as to inform health care providers about thediagnosis of PAI and how to provide treatment for anadrenal crisis; a medical alert bracelet or necklace is alsouseful. All patients should be provided with injectable hy-drocortisone for emergency use. Training in self-injectionis likely to lower the threshold for parenteral hydrocorti-sone use. Rectal suppositories (prednisolone 100 mg) arean alternative for crisis prevention in the absence of diar-rhea. Strong recommendations for patient education and

emergency care were made based on placing a high valueon reducing the morbidity and mortality of adrenal crisisand the knowledge of the existing low awareness levels ofpatients and health professionals. Measures to prevent anadrenal crisis are summarized in Table 4 (122).

5.0 Additional monitoring requirement5.1 We suggest that adults and children with PAI be

seen by an endocrinologist or a healthcare provider withendocrine expertise at least annually. Infants should beseen at least every 3 to 4 months. (Ungraded best practicestatement)

5.2 We suggest that PAI patients be evaluated annuallyfor symptoms and signs of over- and under-replacement.(Ungraded best practice statement)

5.3 We suggest periodic screening for autoimmune dis-eases known to be more prevalent in PAI patients in whomautoimmune origin of PAI has not been excluded. Theoptimal frequency of screening is unknown but can bedone annually. These conditions include thyroid disease,diabetes mellitus, premature ovarian failure, celiac dis-ease, and autoimmune gastritis with vitamin B12 defi-ciency. (2�QQEE)

5.4 We suggest patient education about increasing thedosage of glucocorticoids during intercurrent illness, fe-ver, and stress. This education includes identification ofprecipitating symptoms and signs and how to act in im-pending adrenal crisis. (Ungraded best practice statement)

5.5 We suggest genetic counseling for patients with PAIdue to monogenic disorders. (Ungraded best practicestatement)

EvidenceThe goal of treatment and follow-up of patients with

PAI is to restore normal well-being, stable weight, normalsexual function, and full professional activity. Regularmedical examinations allow evaluation of the physicalcondition of patients with regard to over- or under-re-placement, the correct dosage of the replacement therapy,and HRQoL. Questions on family relations, professionalduties, and self-esteem are relevant. Any adrenal crisisshould be addressed.

The monitoring of replacement therapy is mainly clin-ical. Most patients will attain a normal pigmentation onsufficient replacement therapy. Arterial blood pressureshould be normal and the weight stable. Orthostatic hy-potension indicates insufficient mineralocorticoid therapyor low salt intake.

Routine laboratory analyses should include serum so-dium and potassium determinations. Although not rec-ommended for routine monitoring of glucocorticoid re-placement, measurement of cortisol can be useful to

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obtain evidence of adequate cortisol uptake. Drugs thatincrease the metabolism of cortisol may influence half-life.Plasma renin activity or renin substrate is useful to mon-itor fludrocortisone replacement, which should aim at theupper normal reference range or a slightly elevated value.

Increased prevalence of other autoimmune disordersmay provide a rationale for surveillance, especially auto-immune thyroid disease, which is seen in half of femalesand 25% of males with PAI (7). Type 1 diabetes is presentin 10–15% of patients in Scandinavia (7), but is less fre-quent in other populations (156–158). Therefore, annualassay of TSH, free T4, and HbA1c can help in the identi-fication and treatment of these conditions. Females shouldbe informed of the risk of premature ovarian insufficiency,which was seen in 8% of females in a national Norwegiansurvey (7). In an Italian cohort of 258 women with PAI,20.2% had premature ovarian insufficiency; prematureovarian insufficiency was diagnosed in 20 of 49 (40.8%)with APS-1, six of 18 (33.3%) with APS-4, 26 of 163(16%) with APS-2, but none of 28 with isolated PAI (159).Additional testing can include measurement of CYP11A1autoantibodies (160), the presence of which is correlatedto premature ovarian insufficiency, although the protein isexpressed in all steroidogenic tissues. However, the pre-dictive value of CYP11A1 autoantibodies has not been

assessed. Using the less sensitive immunofluor-escence assay of steroid-cell autoantibodies, Reato et al(159) found that three of 13 seropositive patients devel-oped premature ovarian insufficiency during a mean ob-servation period of 8 years, indicating that the predictivevalue is not that high. Unlike premature ovarian insuffi-ciency caused by nonautoimmune conditions, follicularfunction seems to be retained for up to several years afterdiagnosis in PAI patients (161). This creates a window ofopportunity to sample ovarian tissue for cryopreservationfor further in vitro maturation and subsequent in vitrofertilization. Although this approach is currently experi-mental, further refinement and improved performance ofthese technologies can be expected for the near to midtermfuture.

Other testing to be considered during the annual eval-uation of patients with PAI is a complete blood count.Vitamin B12 deficiency due to autoimmune gastritis iscommon (7, 156), and vitamin B12 levels can also be mon-itored annually. If vitamin B12 deficiency is suspected,further diagnostic workup is warranted (eg, determina-tion of holotranscobalamin, homocysteine, methylma-lonic acid, and/or autoantibodies against parietal cells andintrinsic factor). Because the prevalence of celiac disease inPAI is about 5% (156, 162, 163), screening for tissue

Table 4. Measures for Prevention of Adrenal Crisis

Action Point Intervention

Identify and define theproblem

Steroid emergency card (check that card is available and up to date)Medical alert bracelet or necklace: “Adrenal insufficiency – needs steroids!”

Educate patient (andpartner/parents)

Sick day rule 1: need to double the routine oral glucocorticoid dose when the patientexperiences fever or illness requiring bed rest; when requiring antibiotics for aninfection; or before a small outpatient procedure (eg, dental work)

Sick day rule 2: need to inject a glucocorticoid preparation im or iv in case of severeillness, trauma, persistent vomiting, when fasting for a procedure (colonoscopy!), orduring surgical intervention.

100 mg hydrocortisone iv, im, or sc followed by 200 mg hydrocortisone per continuous ivinfusion, alternatively repeated bolus doses (iv or im) every 6 h

Give special attention to: Explaining the rationale for dose adjustment in stress/sicknessDiscussing the situations requiring dose adjustmentDiscussing symptoms and signs of emergent adrenal crisisTeaching parenteral self-administration of glucocorticoid preparationEnforcing the need to go to hospital after emergency injection

Provide patient with: Sufficient supply of hydrocortisone and fludrocortisone (accounting for possible sick days)Hydrocortisone emergency injection kit prescription (vials of 100 mg hydrocortisone

sodium, syringes, needles; alternatively, also hydrocortisone or prednisolonesuppositories)

Leaflet with information on adrenal crisis and hospitalization to be shown to health carestaff; clearly advise regarding the need to inject 100 mg hydrocortisone immediately ivor im, followed by continuous infusion of 200 mg/24 h

Emergency phone number of endocrine specialist teamFollow-up Reinforce education and confirm understanding during each follow-up visit (at least

annually in a patient without specific problems or recent crises; otherwise, morefrequently)

Adapted from I. Bancos, et al: Diagnosis and management of adrenal insufficiency. Lancet Diabetes Endocrinol. 2015;3:216–226 (122), withpermission. © Elsevier Limited.

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transglutaminase 2 autoantibodies and total IgA can bedone occasionally, even when abdominal symptoms areabsent. Vitiligo and alopecia areata are frequent signs andare considered as markers of autoimmunity.

Other less frequent autoimmune disorders have to betaken into account in some patients with suggestive clin-ical features. Several forms of PAI are familial. Ten percentof Norwegian PAI patients have a relative with autoim-mune PAI. PAI in the context of adrenoleukodystrophy,congenital hypogonadotropic hypogonadism, and con-genital adrenal hypoplasia follow X-linked inheritance,whereas CAH and APS-1 are autosomal recessive (164).

Perspectives and Demand for FutureResearch

Diagnostic procedures and treatment strategies for PAI arestill far from being optimal. There are a number of unre-solved questions regarding the validity of adrenal functiontests in PAI. In particular, confounding factors relate todefining adrenal dysfunction during critical illness andmonitoring adrenal steroids in relation to underlying dis-eases and concurrent medications. Interpreting abnormalstress responses in a range of clinical situations will remainchallenging until appropriate research can identify factorsthat are more diagnostic than cortisol. Two current de-velopments may be of benefit. First, salivary cortisol hasbeen investigated in a number of settings and is showingsome potential as a biomarker. There are some limitationsfrom the collection and analysis perspective, but these canbe dealt with (165). Second, the introduction of more spe-cific diagnostic testing involving liquid chromatography/tandem mass spectrometry (LC-MS/MS) should providebetter standardization in the measurement of cortisol.Suchmethodsarerelatively free fromanalytical interferencesassociatedwithmedicationsanddietary constituents andarenot hampered by the cross-reactivity issues associated withimmunoassays. Although isobaric interferences can occurwith LC-MS/MS, particularly for some steroids with identi-cal elemental formulae, such sources of interference can beavoidedbyappropriate chromatographic separationanduseof multiple mass transitions for identification. Another ma-joradvantageofLC-MS/MSover immunoassays is its abilityto quantify in a single analysis multiple steroids, in somemethods up to 15 or more, thereby substantially broadeningidentification of different forms and underlying causes ofadrenal insufficiency (166).

Regarding treatment of PAI, there are even more un-resolved issues. Despite optimal steroid replacement in-cluding glucocorticoids, mineralocorticoids, and andro-gens as depicted above, a significant number of patients

continue to have objective and subjective complaints. Thisincludes symptoms of over- or under-substitution withglucocorticoids, reduced vitality and perception of generalhealth, and reduced physical function, especially inwomen (3), which translates into reduced working capac-ity. There are also a number metabolic or cardiovascularcomplications including hypertension (167).

Current replacement strategies do not restore the phys-iological feedback regulation of an intact hypothalamic-pituitary-adrenal axis. Circadian and pulsatile hormonesecretion is not normalized. There is an impairment ofadrenomedullary function including the regulation ofcatecholamines and neuropeptides (168). This has beenshown to correlate with cardiovascular instability, hypo-glycemia, and physical activity in patients with PAI due toCAH (169).

Other modified and delayed-release formulations ofhydrocortisone in clinical development aim to mimic thecortisol circadian rhythm (170, 171). Dual and slow-release formulations of cortisol may better mimic circa-dian hormone release (104) but do not mimic the physi-ological pulsatile release of cortisol. Cortisol replacementby means of continuous sc infusion using insulin pumpsprovides a similar circadian rhythm, also mimicking theearly morning increase in cortisol (172, 173). Subcutane-ous infusion utilizing an insulin pump can reconstitute thecircadian variation and was associated with improvementof HRQoL in an open crossover study (173). In a smallerdouble-blind study, no impact on HRQoL was seen (174).Pump treatment is more cumbersome than conventionaltreatment and should be reserved for patients who en-counter major difficulties with conventional treatment.Because the late night nadir and the early morning rise incortisol is attained, ACTH levels can be used as a bio-marker to assess correct dosing (173). Recently, the fea-sibility of pulsatile sc cortisol replacement was studied inhealthy dexamethasone-suppressed individuals (175).There is a great need for large, randomized clinical trialsto increase the evidence base on what is the best gluco-corticoid replacement therapy.

At diagnosis, most PAI patients retain a certain cortisolproduction (176). Treatment of newly diagnosed autoim-mune PAI patients with rituximab (176) and establishedPAI patients with depot tetracosactide (177) has demon-strated that regenerationof cortisol production ispossible.Further exploration of the regenerative potential of adre-nocortical stem cells combined with immunomodulatorytreatment to stop the autoimmune destruction could po-tentially provide the ultimate treatment option in autoim-mune PAI.

Gene therapy may potentially restore the defect in cer-tain forms of monogenic PAI (178), and there is one report

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in the literature on successful adrenal transplantation(179). A great potential may involve novel cell replace-ment and encapsulation technologies (180). This may po-tentially allow a restoration of hypothalamic-pituitary-adrenal axis function and a possible cure for PAI.However, to be successful with such an endeavor, a majorinterdisciplinary effort of physicians, cell biologists, im-munologists, and material scientists will be required.

Financial Disclosures of the Task Force*

Stefan R. Bornstein, MD, PhD, (chair)—Financial or Busi-ness/Organizational Interests: Novo Nordisk, BoehringerIngelheim; Significant Financial Interest or Leadership Po-sition: none declared. Bruno Allolio, MD—Financial orBusiness/Organizational Interests: European Society ofEndocrinology; Significant Financial Interest or Leader-ship Position: Boehringer Ingelheim (Consultant). WiebkeArlt, MD, DSc, FRCP, FMedSci—Financial or Business/Organizational Interests:EuropeanSocietyofEndocrinol-ogy, Society for Endocrinology, Diurnal Limited, JanssenPharmaceutical, Atterocor; Significant Financial Interestor Leadership Position: none declared. Andreas Barthel,MD, MSc—Financial or Business/Organizational Inter-ests: DGE (German Endocrine Society); Significant Finan-cial Interest or Leadership Position: none declared. An-drew Don-Wauchope, MB, BCh, MD, FRCP Edin,FCPath, FRCPath, FRCPC—Financial or Business/Orga-nizational Interests: Institute for Quality Management inHealthcare, Canadian Society for Clinical Chemistry,American Association of Clinical Chemistry; SignificantFinancial Interest or Leadership Position: Canadian As-sociation of Medical Biochemists (Past President). Gary D.Hammer, MD, PhD—Financial or Business/Organiza-tional Interests: ISIS Pharmaceutical, Orphagen, HRAPharma, Embara; Significant Financial Interest or Lead-ership Position: Atterocor (Founder, Owner, Consultant).Eystein Husebye, MD, PhD—Financial or Business/Orga-nizational Interests: none declared; Significant FinancialInterest or Leadership Position: ViroPharma/Shire (Lec-turer). Deborah P. Merke, MS, MD—Financial or Busi-ness/Organizational Interests: Diurnal Limited; Signifi-cant Financial Interest or Leadership Position: nonedeclared. M. Hassan Murad, MD, MPH**—Financial orBusiness/Organizational Interests: Mayo Clinic, Divisionof Preventive Medicine; Significant Financial Interest orLeadership Position: none declared. Constantine A.Stratakis, MD, DSc—Financial or Business/Organiza-tional Interests: none declared; Significant Financial In-terest or Leadership Position: none declared. David J.Torpy, MBBS, PhD, FRACP—Financial or Business/Or-

ganizational Interests: Novartis; Significant Financial In-terest or Leadership Position: None declared.

* Financial, business, and organizational disclosures ofthe Task Force cover the year prior to publication. Dis-closures prior to this time period are archived.

Acknowledgments

The authors of the Diagnosis and Treatment of Primary AdrenalInsufficiency Clinical Practice Guideline dedicate the guidelineto Professor Dr. Bruno Allolio, who suddenly died on August 16,2015. Bruno was a highly respected endocrinologist and brilliantexpert in the adrenal field. Improving the care of patients diag-nosed with adrenal insufficiency was a major driver of his clinicalactivities. We will miss him very much and will keep him in ourmemories as an outstanding colleague and friend.

Address all correspondence and requests for reprints to: TheEndocrine Society, 2055 L Street NW, Suite 600, Washington,DC 20036. E-mail: [email protected]; Phone: 202-971-3636. Send commercial reprint requests for orders over 100 to:https://www.endocrine.org/corporaterelations/commercial-reprints. Send commercial reprint requests for orders under 100to: Society Services. E-mail: society [email protected];Phone: 202-971-3636; Fax: 202-736-9705.

Cosponsoring Associations: European Society of Endocrinol-ogy and the American Association for Clinical Chemistry.

** Evidence-based reviews for this guideline were preparedunder contract with the Endocrine Society.

References

1. Addison T. On the Constitutional and Local Effects of Disease ofthe Supra-renal Capsules. London, UK: Samuel Highley; 1855.

2. Bleicken B, Hahner S, Ventz M, Quinkler M. Delayed diagnosis ofadrenal insufficiency is common: a cross-sectional study in 216patients. Am J Med Sci. 2010;339:525–531.

3. Løvås K, Loge JH, Husebye ES. Subjective health status in Nor-wegian patients with Addison’s disease. Clin Endocrinol (Oxf).2002;56:581–588.

4. Hahner S, Allolio B. Therapeutic management of adrenal insuffi-ciency. Best Pract Res Clin Endocrinol Metab. 2009;23:167–179.

5. Reisch N, Arlt W. Fine tuning for quality of life: 21st century ap-proach to treatment of Addison’s disease. Endocrinol Metab ClinNorth Am. 2009;38:407–418, ix–x.

6. Meyer G, Hackemann A, Penna-Martinez M, Badenhoop K. Whataffects the quality of life in autoimmune Addison’s disease? HormMetab Res. 2013;45:92–95.

7. Erichsen MM, Løvås K, Fougner KJ, et al. Normal overall mortalityrate in Addison’s disease, but young patients are at risk of prema-ture death. Eur J Endocrinol. 2009;160:233–237.

8. Wallace I, Cunningham S, Lindsay J. The diagnosis and investiga-tion of adrenal insufficiency in adults. Ann Clin Biochem. 2009;46:351–367.

9. Chakera AJ, Vaidya B. Addison disease in adults: diagnosis andmanagement. Am J Med. 2010;123:409–413.

10. Laureti S, Vecchi L, Santeusanio F, Falorni A. Is the prevalence ofAddison’s disease underestimated? J Clin Endocrinol Metab. 1999;84:1762.

11. Meyer G, Neumann K, Badenhoop K, Linder R. Increasing prev-

384 Bornstein (chair) et al Guidelines on Primary Adrenal Insufficiency J Clin Endocrinol Metab, February 2016, 101(2):364–389

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 22 January 2017. at 20:38 For personal use only. No other uses without permission. . All rights reserved.

Page 22: Diagnosis and Treatment of Primary Adrenal Insufficiency ... › pediatrics › documents › ACTHStim-Endoso… · 1.3 In patients with severe adrenal insufficiency symptoms or adrenal

alence of Addison’s disease in German females: health insurancedata 2008–2012. Eur J Endocrinol. 2014;170:367–373.

12. Bornstein SR. Predisposing factors for adrenal insufficiency.N Engl J Med. 2009;360:2328–2339.

13. Grossman AB. Clinical review: The diagnosis and management ofcentral hypoadrenalism. J Clin Endocrinol Metab. 2010;95:4855–4863.

14. Speiser PW, Azziz R, Baskin LS, et al. Congenital adrenal hyper-plasia due to steroid 21-hydroxylase deficiency: an Endocrine So-ciety clinical practice guideline. J Clin Endocrinol Metab. 2010;95:4133–4160.

15. Atkins D, Best D, Briss PA, et al. Grading quality of evidence andstrength of recommendations. BMJ. 2004;328:1490.

16. Swiglo BA, Murad MH, Schünemann HJ, et al. A case for clarity,consistency, and helpfulness: state-of-the-art clinical practiceguidelines in endocrinology using the grading of recommendations,assessment, development, and evaluation system. J Clin Endocri-nol Metab. 2008;93:666–673.

17. Guyatt GH, Schünemann HJ, Djulbegovic B, Akl EA. Guidelinepanels should not GRADE good practice statements. J Clin Epi-demiol. 2015;68:597–600.

18. Kazlauskaite R, Evans AT, Villabona CV, et al. Corticotropin testsfor hypothalamic-pituitary-adrenal insufficiency: a metaanalysis.J Clin Endocrinol Metab. 2008;93:4245–4253.

19. Oelkers W, Boelke T, Bähr V. Dose-response relationships be-tween plasma adrenocorticotropin (ACTH), cortisol, aldosterone,and 18-hydroxycorticosterone after injection of ACTH-(1–39) orhuman corticotropin-releasing hormone in man. J Clin EndocrinolMetab. 1988;66:181–186.

20. Lee MK, Vasikaran S, Doery JC, Wijeratne N, Prentice D. Cortisol:ACTH ratio to test for primary hypoadrenalism: a pilot study.Postgrad Med J. 2013;89:617–620.

21. Wood JB, Frankland AW, James VH, Landon J. A rapid test ofadrenocortical function. Lancet. 1965;1:243–245.

22. Abdu TA, Elhadd TA, Neary R, Clayton RN. Comparison of thelow dose short synacthen test (1 microg), the conventional doseshort synacthen test (250 microg), and the insulin tolerance test forassessment of the hypothalamo-pituitary-adrenal axis in patientswith pituitary disease. J Clin Endocrinol Metab. 1999;84:838–843.

23. Schmidt IL, Lahner H, Mann K, Petersenn S. Diagnosis of adrenalinsufficiency: evaluation of the corticotropin-releasing hormonetest and basal serum cortisol in comparison to the insulin tolerancetest in patients with hypothalamic-pituitary-adrenal disease. J ClinEndocrinol Metab. 2003;88:4193–4198.

24. Deutschbein T, Unger N, Mann K, Petersenn S. Diagnosis of sec-ondary adrenal insufficiency in patients with hypothalamic-pitu-itary disease: comparison between serum and salivary cortisol dur-ing the high-dose short synacthen test. Eur J Endocrinol. 2009;160:9–16.

25. Cho HY, Kim JH, Kim SW, et al. Different cut-off values of theinsulin tolerance test, the high-dose short Synacthen test (250 �g)and the low-dose short Synacthen test (1 �g) in assessing centraladrenal insufficiency. Clin Endocrinol (Oxf). 2014;81:77–84.

26. Chatha KK, Middle JG, Kilpatrick ES. National UK audit of theshort synacthen test. Ann Clin Biochem. 2010;47:158–164.

27. Reynolds RM, Stewart PM, Seckl JR, Padfield PL. Assessing theHPA axis in patients with pituitary disease: a UK survey. ClinEndocrinol (Oxf). 2006;64:82–85.

28. Grinspoon SK, Biller BM. Clinical review 62: Laboratory assess-ment of adrenal insufficiency. J Clin Endocrinol Metab. 1994;79:923–931.

29. Dorin RI, Qualls CR, Crapo LM. Diagnosis of adrenal insuffi-ciency. Ann Intern Med. 2003;139:194–204.

30. Gundgurthi A, Garg MK, Dutta MK, Pakhetra R. IntramuscularACTH stimulation test for assessment of adrenal function. J AssocPhysicians India. 2013;61:320–324.

31. Bhansali A, Subrahmanyam KA, Talwar V, Dash RJ. Plasma cor-

tisol response to 1 microgram adrenocorticotropin at 0800 h &1600 h in healthy subjects. Indian J Med Res. 2001;114:173–176.

32. Dickstein G, Shechner C, Nicholson WE, et al. Adrenocorticotro-pin stimulation test: effects of basal cortisol level, time of day, andsuggested new sensitive low dose test. J Clin Endocrinol Metab.1991;72:773–778.

33. Charmandari E, Kino T. Chrousos syndrome: a seminal report, aphylogenetic enigma and the clinical implications of glucocorticoidsignalling changes. Eur J Clin Invest. 2010;40:932–942.

34. Charmandari E, Kino T, Chrousos GP. Primary generalized famil-ial and sporadic glucocorticoid resistance (Chrousos syndrome)and hypersensitivity. Endocr Dev. 2013;24:67–85.

35. Torpy DJ, Bachmann AW, Grice JE, et al. Familial corticosteroid-binding globulin deficiency due to a novel null mutation: associa-tion with fatigue and relative hypotension. J Clin EndocrinolMetab. 2001;86:3692–3700.

36. Gagliardi L, Ho JT, Torpy DJ. Corticosteroid-binding globulin:the clinical significance of altered levels and heritable mutations.Mol Cell Endocrinol. 2010;316:24–34.

37. Jones DA, Miras A, Tringham JR. Addison’s disease: a diagnosticchallenge. Br J Hosp Med (Lond). 2008;69:M192–M195.

38. Oelkers W, Diederich S, Bähr V. Diagnosis and therapy surveil-lance in Addison’s disease: rapid adrenocorticotropin (ACTH) testand measurement of plasma ACTH, renin activity, and aldoste-rone. J Clin Endocrinol Metab. 1992;75:259–264.

39. Oelkers W. Adrenal insufficiency. N Engl J Med. 1996;335:1206–1212.

40. Lebbe M, Arlt W. What is the best diagnostic and therapeuticmanagement strategy for an Addison patient during pregnancy?Clin Endocrinol (Oxf). 2013;78:497–502.

41. Suri D, Moran J, Hibbard JU, Kasza K, Weiss RE. Assessment ofadrenal reserve in pregnancy: defining the normal response to theadrenocorticotropin stimulation test. J Clin Endocrinol Metab.2006;91:3866–3872.

42. Jung C, Ho JT, Torpy DJ, et al. A longitudinal study of plasma andurinary cortisol in pregnancy and postpartum. J Clin EndocrinolMetab. 2011;96:1533–1540.

43. Klose M, Lange M, Rasmussen AK, et al. Factors influencing theadrenocorticotropin test: role of contemporary cortisol assays,body composition, and oral contraceptive agents. J Clin Endocri-nol Metab. 2007;92:1326–1333.

44. El-Farhan N, Pickett A, Ducroq D, et al. Method-specific serumcortisol responses to the adrenocorticotrophin test: comparison ofgas chromatography-mass spectrometry and five automated im-munoassays. Clin Endocrinol (Oxf). 2013;78:673–680.

45. May ME, Carey RM. Rapid adrenocorticotropic hormone test inpractice. Retrospective review. Am J Med. 1985;79:679–684.

46. Oelkers W. The role of high- and low-dose corticotropin tests in thediagnosis of secondary adrenal insufficiency. Eur J Endocrinol.1998;139:567–570.

47. Magnotti M, Shimshi M. Diagnosing adrenal insufficiency: whichtest is best–the 1-microg or the 250-microg cosyntropin stimula-tion test? Endocr Pract. 2008;14:233–238.

48. Dhillo WS, Kong WM, Le Roux CW, et al. Cortisol-binding glob-ulin is important in the interpretation of dynamic tests of the hy-pothalamic–pituitary–adrenal axis. Eur J Endocrinol. 2002;146:231–235.

49. Mueller UW, Potter J. Binding of cortisol to human albumin andserum: the effect of protein concentration. Biochem Pharmacol.1981;30:727–733.

50. Vincent RP, Etogo-Asse FE, Dew T, Bernal W, Alaghband-ZadehJ, le Roux CW. Serum total cortisol and free cortisol index givedifferent information regarding the hypothalamus-pituitary-adre-nal axis reserve in patients with liver impairment. Ann ClinBiochem. 2009;46:505–507.

51. le Roux CW, Chapman GA, Kong WM, Dhillo WS, Jones J, Alagh-band-Zadeh J. Free cortisol index is better than serum total cortisolin determining hypothalamic-pituitary-adrenal status in patients

doi: 10.1210/jc.2015-1710 press.endocrine.org/journal/jcem 385

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 22 January 2017. at 20:38 For personal use only. No other uses without permission. . All rights reserved.

Page 23: Diagnosis and Treatment of Primary Adrenal Insufficiency ... › pediatrics › documents › ACTHStim-Endoso… · 1.3 In patients with severe adrenal insufficiency symptoms or adrenal

undergoing surgery. J Clin Endocrinol Metab. 2003;88:2045–2048.

52. Hamrahian AH, Oseni TS, Arafah BM. Measurements of serumfree cortisol in critically ill patients. N Engl J Med. 2004;350:1629–1638.

53. Pura M, Kreze A Jr, Kentos P, Vanuga P. The low-dose (1 microg)cosyntropin test (LDT) for primary adrenocortical insufficiency:defining the normal cortisol response and report on first patientswith Addison disease confirmed with LDT. Exp Clin EndocrinolDiabetes. 2010;118:151–157.

54. Mayenknecht J, Diederich S, Bähr V, et al. Comparison of low andhigh dose corticotropin stimulation tests in patients with pituitarydisease. J Clin Endocrinol Metab. 1998;83:1558–1562.

55. Chitale A, Musonda P, McGregor AM, Dhatariya KK. Determin-ing the utility of the 60 min cortisol measurement in the shortsynacthen test. Clin Endocrinol (Oxf). 2013;79:14–19.

56. Lindholm J, Kehlet H. Re-evaluation of the clinical value of the 30min ACTH test in assessing the hypothalamic-pituitary-adreno-cortical function. Clin Endocrinol (Oxf). 1987;26:53–59.

57. Dekkers OM, Timmermans JM, Smit JW, Romijn JA, Pereira AM.Comparison of the cortisol responses to testing with two doses ofACTH in patients with suspected adrenal insufficiency. Eur J En-docrinol. 2011;164:83–87.

58. Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely illpatients. N Engl J Med. 2003;348:727–734.

59. Marik PE, Pastores SM, Annane D, et al. Recommendations for thediagnosis and management of corticosteroid insufficiency in crit-ically ill adult patients: consensus statements from an internationaltask force by the American College of Critical Care Medicine. CritCare Med. 2008;36:1937–1949.

60. Anantharaman R, Menezes G, Yusuf R, Ganapathi B, Ayyar SV,Srinivasan R. The 1 �g cosyntropin test in normal individuals: areappraisal. Indian J Endocrinol Metab. 2013;17:693–696.

61. Watts NB, Tindall GT. Rapid assessment of corticotropin reserveafter pituitary surgery. JAMA. 1988;259:708–711.

62. Erturk E, Jaffe CA, Barkan AL. Evaluation of the integrity of thehypothalamic-pituitary-adrenal axis by insulin hypoglycemia test.J Clin Endocrinol Metab. 1998;83:2350–2354.

63. Jones SL, Trainer PJ, Perry L, Wass JA, Bessser GM, Grossman A.An audit of the insulin tolerance test in adult subjects in an acuteinvestigation unit over one year. Clin Endocrinol (Oxf). 1994;41:123–128.

64. Le Roux CW, Meeran K, Alaghband-Zadeh J. Is a 0900-h serumcortisol useful prior to a short Synacthen test in outpatient assess-ment? Ann Clin Biochem. 2002;39:148–150.

65. Endert E, Ouwehand A, Fliers E, Prummel MF, Wiersinga WM.Establishment of reference values for endocrine tests. Part IV: Ad-renal insufficiency. Neth J Med. 2005;63:435–443.

66. Jenkins D, Forsham PH, Laidlaw JC, Reddy WJ, Thorn GW. Useof ACTH in the diagnosis of adrenal cortical insufficiency. Am JMed. 1955;18:3–14.

67. Hägg E, Asplund K, Lithner F. Value of basal plasma cortisol assaysin the assessment of pituitary-adrenal insufficiency. Clin Endocri-nol (Oxf). 1987;26:221–226.

68. Baker PR, Baschal EE, Fain PR, et al. Haplotype analysis discrim-inates genetic risk for DR3-associated endocrine autoimmunityand helps define extreme risk for Addison’s disease. J Clin Endo-crinol Metab. 2010;95:E263–E270.

69. Van Rijn JL, Van Landeghem BA, Haima P, Goldschmidt HM.Evaluation of ACTH immunoradiometric assays. Clin Biochem.1996;29:93–95.

70. Pecori Giraldi F, Saccani A, Cavagnini F. Assessment of ACTHassay variability: a multicenter study. Eur J Endocrinol. 2011;164:505–512.

71. Saenger P, Levine LS, Irvine WJ, et al. Progressive adrenal failurein polyglandular autoimmune disease. J Clin Endocrinol Metab.1982;54:863–867.

72. Coco G, Dal Pra C, Presotto F, et al. Estimated risk for developing

autoimmune Addison’s disease in patients with adrenal cortex au-toantibodies. J Clin Endocrinol Metab. 2006;91:1637–1645.

73. De Bellis A, Bizzarro A, Rossi R, et al. Remission of subclinicaladrenocortical failure in subjects with adrenal autoantibodies.J Clin Endocrinol Metab. 1993;76:1002–1007.

74. Betterle C, Scalici C, Presotto F, et al. The natural history of adrenalfunction in autoimmune patients with adrenal autoantibodies.J Endocrinol. 1988;117:467–475.

75. Rehan M, Raizman JE, Cavalier E, Don-Wauchope AC, HolmesDT. Laboratory challenges in primary aldosteronism screening anddiagnosis. Clin Biochem. 2015;48:377–387.

76. Conrad K, Roggenbuck D, Reinhold D, Sack U. Autoantibodydiagnostics in clinical practice. Autoimmun Rev. 2012;11:207–211.

77. Winqvist O, Karlsson FA, Kämpe O. 21-Hydroxylase, a majorautoantigen in idiopathic Addison’s disease. Lancet. 1992;339:1559–1562.

78. Laureti S, De Bellis A, Muccitelli VI, et al. Levels of adrenocorticalautoantibodies correlate with the degree of adrenal dysfunction insubjects with preclinical Addison’s disease. J Clin EndocrinolMetab. 1998;83:3507–3511.

79. Laureti S, Aubourg P, Calcinaro F, et al. Etiological diagnosis ofprimary adrenal insufficiency using an original flowchart of im-mune and biochemical markers. J Clin Endocrinol Metab. 1998;83:3163–3168.

80. Meager A, Visvalingam K, Peterson P, et al. Anti-interferon auto-antibodies in autoimmune polyendocrinopathy syndrome type 1.PLoS Med. 2006;3:e289.

81. Laureti S, Casucci G, Santeusanio F, Angeletti G, Aubourg P, Bru-netti P. X-linked adrenoleukodystrophy is a frequent cause of id-iopathic Addison’s disease in young adult male patients. J ClinEndocrinol Metab. 1996;81:470–474.

82. Horn MA, Erichsen MM, Wolff AS, et al. Screening for X-linkedadrenoleukodystrophy among adult men with Addison’s disease.Clin Endocrinol (Oxf). 2013;79:316–320.

83. Vita JA, Silverberg SJ, Goland RS, Austin JH, Knowlton AI. Clin-ical clues to the cause of Addison’s disease. Am J Med. 1985;78:461–466.

84. Knutsson U, Dahlgren J, Marcus C, et al. Circadian cortisolrhythms in healthy boys and girls: relationship with age, growth,body composition, and pubertal development. J Clin EndocrinolMetab. 1997;82:536–540.

85. Linder BL, Esteban NV, Yergey AL, Winterer JC, Loriaux DL,Cassorla F. Cortisol production rate in childhood and adolescence.J Pediatr. 1990;117:892–896.

86. Esteban NV, Loughlin T, Yergey AL, et al. Daily cortisol produc-tion rate in man determined by stable isotope dilution/mass spec-trometry. J Clin Endocrinol Metab. 1991;72:39–45.

87. Kerrigan JR, Veldhuis JD, Leyo SA, Iranmanesh A, Rogol AD.Estimation of daily cortisol production and clearance rates in nor-mal pubertal males by deconvolution analysis. J Clin EndocrinolMetab. 1993;76:1505–1510.

88. Purnell JQ, Brandon DD, Isabelle LM, Loriaux DL, Samuels MH.Association of 24-hour cortisol production rates, cortisol-bindingglobulin, and plasma-free cortisol levels with body composition,leptin levels, and aging in adult men and women. J Clin EndocrinolMetab. 2004;89:281–287.

89. Allolio B, Winkelmann W, Fricke U, Heesen D, Kaulen D. Cortisolplasma concentration in patients with primary adrenal cortex in-sufficiency during substitution therapy with cortisone acetate [inGerman]. Verh Dtsch Ges Inn Med. 1978;84:1456–1458.

90. Czock D, Keller F, Rasche FM, Häussler U. Pharmacokinetics andpharmacodynamics of systemically administered glucocorticoids.Clin Pharmacokinet. 2005;44:61–98.

91. Plat L, Leproult R, L’Hermite-Baleriaux M, et al. Metabolic effectsof short-term elevations of plasma cortisol are more pronounced inthe evening than in the morning. J Clin Endocrinol Metab. 1999;84:3082–3092.

386 Bornstein (chair) et al Guidelines on Primary Adrenal Insufficiency J Clin Endocrinol Metab, February 2016, 101(2):364–389

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92. Simon N, Castinetti F, Ouliac F, Lesavre N, Brue T, Oliver C.Pharmacokinetic evidence for suboptimal treatment of adrenal in-sufficiency with currently available hydrocortisone tablets. ClinPharmacokinet. 2010;49:455–463.

93. Peacey SR, Guo CY, Robinson AM, et al. Glucocorticoid replace-ment therapy: are patients over treated and does it matter? ClinEndocrinol (Oxf). 1997;46:255–261.

94. Howlett TA. An assessment of optimal hydrocortisone replace-ment therapy. Clin Endocrinol (Oxf). 1997;46:263–268.

95. Mah PM, Jenkins RC, Rostami-Hodjegan A, et al. Weight-relateddosing, timing and monitoring hydrocortisone replacement ther-apy in patients with adrenal insufficiency. Clin Endocrinol (Oxf).2004;61:367–375.

96. Laureti S, Falorni A, Santeusanio F. Improvement of treatment ofprimary adrenal insufficiency by administration of cortisone ace-tate in three daily doses. J Endocrinol Invest. 2003;26:1071–1075.

97. Barbetta L, Dall’Asta C, Re T, Libè R, Costa E, Ambrosi B. Com-parison of different regimens of glucocorticoid replacement ther-apy in patients with hypoadrenalism. J Endocrinol Invest. 2005;28:632–637.

98. Ekman B, Bachrach-Lindström M, Lindström T, Wahlberg J,Blomgren J, Arnqvist HJ. A randomized, double-blind, crossoverstudy comparing two- and four-dose hydrocortisone regimen withregard to quality of life, cortisol and ACTH profiles in patients withprimary adrenal insufficiency. Clin Endocrinol (Oxf). 2012;77:18–25.

99. Alonso N, Granada ML, Lucas A, et al. Evaluation of two replace-ment regimens in primary adrenal insufficiency patients. Effect onclinical symptoms, health-related quality of life and biochemicalparameters. J Endocrinol Invest. 2004;27:449–454.

100. Forss M, Batcheller G, Skrtic S, Johannsson G. Current practice ofglucocorticoid replacement therapy and patient-perceived healthoutcomes in adrenal insufficiency - a worldwide patient survey.BMC Endocr Disord. 2012;12:8.

101. Fariss BL, Hane S, Shinsako J, Forsham PH. Comparison of ab-sorption of cortisone acetate and hydrocortisone hemisuccinate.J Clin Endocrinol Metab. 1978;47:1137–1140.

102. Filipsson H, Monson JP, Koltowska-Häggström M, Mattsson A,Johannsson G. The impact of glucocorticoid replacement regimenson metabolic outcome and comorbidity in hypopituitary patients.J Clin Endocrinol Metab. 2006;91:3954–3961.

103. Fadeev VV, Gitel EP, Mel’nichenko GA. The diurnal rhythm ofadrenocorticotropic hormone secretion in the assessment of theadequacy of replacement therapy in primary chronic adrenal fail-ure. Neurosci Behav Physiol. 2001;31:237–242.

104. Johannsson G, Nilsson AG, Bergthorsdottir R, et al. Improvedcortisol exposure-time profile and outcome in patients with adre-nal insufficiency: a prospective randomized trial of a novel hydro-cortisone dual-release formulation. J Clin Endocrinol Metab.2012;97:473–481.

105. Williams GH, Cain JP, Dluhy RG, Underwood RH. Studies of thecontrol of plasma aldosterone concentration in normal man. I.Response to posture, acute and chronic volume depletion, andsodium loading. J Clin Invest. 1972;51:1731–1742.

106. Miller WL, Auchus RJ. The molecular biology, biochemistry, andphysiology of human steroidogenesis and its disorders. EndocrRev. 2011;32:81–151.

107. Oelkers W, L’Age M. Control of mineralocorticoid substitution inAddison’s disease by plasma renin measurement. Klin Wochen-schr. 1976;54:607–612.

108. Flad TM, Conway JD, Cunningham SK, McKenna TJ. The role ofplasma renin activity in evaluating the adequacy of mineralocor-ticoid replacement in primary adrenal insufficiency. Clin Endocri-nol (Oxf). 1996;45:529–534.

109. Methlie P, Husebye EE, Hustad S, Lien EA, Løvås K. Grapefruitjuice and licorice increase cortisol availability in patients with Ad-dison’s disease. Eur J Endocrinol. 2011;165:761–769.

110. Keilholz U, Guthrie GP Jr. Adverse effect of phenytoin on miner-

alocorticoid replacement with fludrocortisone in adrenal insuffi-ciency. Am J Med Sci. 1986;291:280–283.

111. Ross IL, Bergthorsdottir R, Levitt N, et al. Cardiovascular riskfactors in patients with Addison’s disease: a comparative study ofSouth African and Swedish patients. PLoS One. 2014;9:e90768.

112. Inder WJ, Meyer C, Hunt PJ. Management of hypertension andheart failure in patients with Addison’s disease. Clin Endocrinol(Oxf). 2015;82:789–792.

113. Orentreich N, Brind JL, Rizer RL, Vogelman JH. Age changes andsex differences in serum dehydroepiandrosterone sulfate concen-trations throughout adulthood. J Clin Endocrinol Metab. 1984;59:551–555.

114. Arlt W, Callies F, van Vlijmen JC, et al. Dehydroepiandrosteronereplacement in women with adrenal insufficiency. N Engl J Med.1999;341:1013–1020.

115. Hunt PJ, Gurnell EM, Huppert FA, et al. Improvement in moodand fatigue after dehydroepiandrosterone replacement in Addi-son’s disease in a randomized, double blind trial. J Clin EndocrinolMetab. 2000;85:4650–4656.

116. Christiansen JJ, Bruun JM, Christiansen JS, Jørgensen JO,Gravholt CH. Long-term DHEA substitution in female adreno-cortical failure, body composition, muscle function, and bone me-tabolism: a randomized trial. Eur J Endocrinol. 2011;165:293–300.

117. Alkatib AA, Cosma M, Elamin MB, et al. A systematic review andmeta-analysis of randomized placebo-controlled trials of DHEAtreatment effects on quality of life in women with adrenal insuffi-ciency. J Clin Endocrinol Metab. 2009;94:3676–3681.

118. Binder G, Weber S, Ehrismann M, et al. Effects of dehydroepi-androsterone therapy on pubic hair growth and psychologicalwell-being in adolescent girls and young women with central ad-renal insufficiency: a double-blind, randomized, placebo-con-trolled phase III trial. J Clin Endocrinol Metab. 2009;94:1182–1190.

119. Allolio B, Hoffmann J, Linton EA, Winkelmann W, Kusche M,Schulte HM. Diurnal salivary cortisol patterns during pregnancyand after delivery: relationship to plasma corticotrophin-releasing-hormone. Clin Endocrinol (Oxf). 1990;33:279–289.

120. Hahner S, Loeffler M, Bleicken B, et al. Epidemiology of adrenalcrisis in chronic adrenal insufficiency: the need for new preventionstrategies. Eur J Endocrinol. 2010;162:597–602.

121. Zelissen PM, Croughs RJ, van Rijk PP, Raymakers JA. Effect ofglucocorticoid replacement therapy on bone mineral density inpatients with Addison disease. Ann Intern Med. 1994;120:207–210.

122. Bancos I, Hahner S, Tomlinson J, Arlt W. Diagnosis and manage-ment of adrenal insufficiency. Lancet Diabetes Endocrinol. 2015;3:216–226.

123. Wiegand S, Richardt A, Remer T, et al. Reduced 11�-hydroxys-teroid dehydrogenase type 1 activity in obese boys. Eur J Endo-crinol. 2007;157:319–324.

124. Bonfig W, Pozza SB, Schmidt H, Pagel P, Knorr D, Schwarz HP.Hydrocortisone dosing during puberty in patients with classicalcongenital adrenal hyperplasia: an evidence-based recommenda-tion. J Clin Endocrinol Metab. 2009;94:3882–3888.

125. Grigorescu-Sido A, Bettendorf M, Schulze E, Duncea I, Heinrich U.Growth analysis in patients with 21-hydroxylase deficiency in-fluence of glucocorticoid dosage, age at diagnosis, phenotypeand genotype on growth and height outcome. Horm Res. 2003;60:84 –90.

126. Allolio B. Extensive expertise in endocrinology: adrenal crisis. EurJ Endocrinol. 2015;172:R115–R124.

127. White K, Arlt W. Adrenal crisis in treated Addison’s disease: apredictable but under-managed event. Eur J Endocrinol. 2010;162:115–120.

128. Hahner S, Spinnler C, Fassnacht M, et al. High incidence of adrenalcrisis in educated patients with chronic adrenal insufficiency: aprospective study. J Clin Endocrinol Metab. 2015;100:407–416.

doi: 10.1210/jc.2015-1710 press.endocrine.org/journal/jcem 387

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129. Reisch N, Willige M, Kohn D, et al. Frequency and causes of ad-renal crises over lifetime in patients with 21-hydroxylase defi-ciency. Eur J Endocrinol. 2012;167:35–42.

130. Fonseca V, Brown R, Hochhauser D, Ginsburg J, Havard CW.Acute adrenal crisis precipitated by thyroxine. Br Med J (Clin ResEd). 1986;292:1185–1186.

131. Chortis V, Taylor AE, Schneider P, et al. Mitotane therapy in ad-renocortical cancer induces CYP3A4 and inhibits 5�-reductase,explaining the need for personalized glucocorticoid and androgenreplacement. J Clin Endocrinol Metab. 2013;98:161–171.

132. Goldfien A, Laidlaw JC, Haydar NA, Renold AE, Thorn GW.Fluorohydrocortisone and chlorohydrocortisone, highly potentderivatives of compound F. N Engl J Med. 1955;252:415–421.

133. Renold AE, Haydar NA, Reddy WJ, Goldfien A, St Marc JR, Laid-law JC. Biological effects of fluorinated derivatives of hydrocorti-sone and progesterone in man. Ann NY Acad Sci. 1955;61:582–590.

134. Thorn GW, Renold AE, Morse WI, Goldfien A, Reddy WJ. Highlypotent adrenal cortical steroids: structure and biological activity.Ann Intern Med. 1955;43:979–1000.

135. Weise M, Drinkard B, Mehlinger SL, et al. Stress dose of hydro-cortisone is not beneficial in patients with classic congenital adre-nal hyperplasia undergoing short-term, high-intensity exercise.J Clin Endocrinol Metab. 2004;89:3679–3684.

136. Quinkler M, Hahner S. What is the best long-term managementstrategy for patients with primary adrenal insufficiency? Clin En-docrinol (Oxf). 2012;76:21–25.

137. Chernow B, Alexander HR, Smallridge RC, et al. Hormonal re-sponses to graded surgical stress. Arch Intern Med. 1987;147:1273–1278.

138. Udelsman R, Norton JA, Jelenich SE, et al. Responses of the hy-pothalamic-pituitary-adrenal and renin-angiotensin axes and thesympathetic system during controlled surgical and anestheticstress. J Clin Endocrinol Metab. 1987;64:986–994.

139. Rains PC, Rampersad N, De Lima J, et al. Cortisol response togeneral anaesthesia for medical imaging in children. Clin Endo-crinol (Oxf). 2009;71:834–839.

140. Hsu AA, von Elten K, Chan D, et al. Characterization of the cortisolstress response to sedation and anesthesia in children. J Clin En-docrinol Metab. 2012;97:E1830–E1835.

141. Taylor LK, Auchus RJ, Baskin LS, Miller WL. Cortisol response tooperative stress with anesthesia in healthy children. J Clin Endo-crinol Metab. 2013;98:3687–3693.

142. Sapolsky RM, Romero LM, Munck AU. How do glucocorticoidsinfluence stress responses? Integrating permissive, suppressive,stimulatory, and preparative actions. Endocr Rev. 2000;21:55– 89.

143. Koniaris LG, Wand G, Wright TM. TNF mediates a murine modelof Addison’s crisis. Shock. 2001;15:29–34.

144. Salem M, Tainsh RE Jr, Bromberg J, Loriaux DL, Chernow B.Perioperative glucocorticoid coverage. A reassessment 42 yearsafter emergence of a problem. Ann Surg. 1994;219:416–425.

145. Glowniak JV, Loriaux DL. A double-blind study of perioperativesteroid requirements in secondary adrenal insufficiency. Surgery.1997;121:123–129.

146. Boonen E, Vervenne H, Meersseman P, et al. Reduced cortisolmetabolism during critical illness. N Engl J Med. 2013;368:1477–1488.

147. Hahner S, Burger-Stritt S, Allolio B. Subcutaneous hydrocortisoneadministration for emergency use in adrenal insufficiency. Eur JEndocrinol. 2013;169:147–154.

148. Hahner S, Hemmelmann N, Quinkler M, Beuschlein F, Spinnler C,Allolio B. Timelines in the management of adrenal crisis - targets,limits and reality. Clin Endocrinol (Oxf). 2015;82:497–502.

149. Bergthorsdottir R, Leonsson-Zachrisson M, Odén A, JohannssonG. Premature mortality in patients with Addison’s disease: a pop-ulation-based study. J Clin Endocrinol Metab. 2006;91:4849–4853.

150. Bensing S, Brandt L, Tabaroj F, et al. Increased death risk andaltered cancer incidence pattern in patients with isolated or com-bined autoimmune primary adrenocortical insufficiency. Clin En-docrinol (Oxf). 2008;69:697–704.

151. Repping-Wuts HJ, Stikkelbroeck NM, Noordzij A, Kerstens M,Hermus AR. A glucocorticoid education group meeting: an effec-tive strategy for improving self-management to prevent adrenalcrisis. Eur J Endocrinol. 2013;169:17–22.

152. Harsch IA, Schuller A, Hahn EG, Hensen J. Cortisone replacementtherapy in endocrine disorders - quality of self-care. J Eval ClinPract. 2010;16:492–498.

153. Braatvedt GD, Newrick PG, Corrall RJ. Patients’ self administra-tion of hydrocortisone. BMJ. 1990;301:1312.

154. Fleming LK, Rapp CG, Sloane R. Caregiver knowledge and self-confidence of stress dosing of hydrocortisone in children with con-genital adrenal hyperplasia. J Pediatr Nurs. 2011;26:e55–e60.

155. Quinkler M, Dahlqvist P, Husebye ES, Kämpe O. A EuropeanEmergency Card for adrenal insufficiency can save lives. Eur J In-tern Med. 2015;26:75–76.

156. Fichna M, Fichna P, Gryczynska M, et al. Screening for associatedautoimmune disorders in Polish patients with Addison’s disease.Endocrine. 2010;37:349–360.

157. Zelissen PM, Bast EJ, Croughs RJ. Associated autoimmunity inAddison’s disease. J Autoimmun. 1995;8:121–130.

158. Betterle C, Scarpa R, Garelli S, et al. Addison’s disease: a survey on633 patients in Padova. Eur J Endocrinol. 2013;169:773–784.

159. Reato G, Morlin L, Chen S, et al. Premature ovarian failure inpatients with autoimmune Addison’s disease: clinical, genetic, andimmunological evaluation. J Clin Endocrinol Metab. 2011;96:E1255–E1261.

160. Winqvist O, Gustafsson J, Rorsman F, Karlsson FA, Kämpe O.Two different cytochrome P450 enzymes are the adrenal antigensin autoimmune polyendocrine syndrome type I and Addison’s dis-ease. J Clin Invest. 1993;92:2377–2385.

161. Falorni A, Brozzetti A, Aglietti MC, et al. Progressive decline ofresidual follicle pool after clinical diagnosis of autoimmune ovar-ian insufficiency. Clin Endocrinol (Oxf). 2012;77:453–458.

162. Myhre AG, Aarsetøy H, Undlien DE, Hovdenak N, Aksnes L,Husebye ES. High frequency of coeliac disease among patients withautoimmune adrenocortical failure. Scand J Gastroenterol. 2003;38:511–515.

163. Betterle C, Lazzarotto F, Spadaccino AC, et al. Celiac disease inNorth Italian patients with autoimmune Addison’s disease. Eur JEndocrinol. 2006;154:275–279.

164. Charmandari E, Nicolaides NC, Chrousos GP. Adrenal insuffi-ciency. Lancet. 2014;383:2152–2167.

165. Raff H. Utility of salivary cortisol measurements in Cushing’s syn-drome and adrenal insufficiency. J Clin Endocrinol Metab. 2009;94:3647–3655.

166. Keevil BG. Novel liquid chromatography tandem mass spectrom-etry (LC-MS/MS) methods for measuring steroids. Best Pract ResClin Endocrinol Metab. 2013;27:663–674.

167. Giordano R, Marzotti S, Balbo M, et al. Metabolic and cardio-vascular profile in patients with Addison’s disease under conven-tional glucocorticoid replacement. J Endocrinol Invest. 2009;32:917–923.

168. Bornstein SR, Breidert M, Ehrhart-Bornstein M, Kloos B,Scherbaum WA. Plasma catecholamines in patients with Addison’sdisease. Clin Endocrinol (Oxf). 1995;42:215–218.

169. Merke DP, Chrousos GP, Eisenhofer G, et al. Adrenomedullarydysplasia and hypofunction in patients with classic 21-hydroxylasedeficiency. N Engl J Med. 2000;343:1362–1368.

170. Newell-Price J, Whiteman M, Rostami-Hodjegan A, et al. Modi-fied-release hydrocortisone for circadian therapy: a proof-of-prin-ciple study in dexamethasone-suppressed normal volunteers. ClinEndocrinol (Oxf). 2008;68:130–135.

171. Mallappa A, Sinaii N, Kumar P, et al. A phase 2 study of Chro-nocort, a modified-release formulation of hydrocortisone, in the

388 Bornstein (chair) et al Guidelines on Primary Adrenal Insufficiency J Clin Endocrinol Metab, February 2016, 101(2):364–389

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treatment of adults with classic congenital adrenal hyperplasia.J Clin Endocrinol Metab. 2015;100:1137–1145.

172. Løvås K, Husebye ES. Continuous subcutaneous hydrocortisoneinfusion in Addison’s disease. Eur J Endocrinol. 2007;157:109–112.

173. Oksnes M, Björnsdottir S, Isaksson M, et al. Continuous subcu-taneous hydrocortisone infusion versus oral hydrocortisone re-placement for treatment of Addison’s disease: a randomized clin-ical trial. J Clin Endocrinol Metab. 2014;99:1665–1674.

174. Gagliardi L, Nenke MA, Thynne TR, et al. Continuous subcuta-neous hydrocortisone infusion therapy in Addison’s disease: a ran-domized, placebo-controlled clinical trial. J Clin EndocrinolMetab. 2014;99:4149–4157.

175. Russell GM, Durant C, Ataya A, et al. Subcutaneous pulsatile glu-cocorticoid replacement therapy. Clin Endocrinol (Oxf). 2014;81:289–293.

176. Pearce SH, Mitchell AL, Bennett S, et al. Adrenal steroidogenesisafter B lymphocyte depletion therapy in new-onset Addison’s dis-ease. J Clin Endocrinol Metab. 2012;97:E1927–E1932.

177. Gan EH, MacArthur K, Mitchell AL, et al. Residual adrenal func-tion in autoimmune Addison’s disease: improvement after tetra-cosactide (ACTH1–24) treatment. J Clin Endocrinol Metab. 2014;99:111–118.

178. Tajima T, Okada T, Ma XM, Ramsey W, Bornstein S, Aguilera G.Restoration of adrenal steroidogenesis by adenovirus-mediatedtransfer of human cytochrome P450 21-hydroxylase into the ad-renal gland of 21-hydroxylase-deficient mice. Gene Ther. 1999;6:1898–1903.

179. Grodstein E, Hardy MA, Goldstein MJ. A case of human intra-muscular adrenal gland transplantation as a cure for chronic ad-renal insufficiency. Am J Transplant. 2010;10:431–433.

180. Ludwig B, Reichel A, Steffen A, et al. Transplantation of humanislets without immunosuppression. Proc Natl Acad Sci USA. 2013;110:19054–19058.

181. Husebye ES, Allolio B, Arlt W, et al. Consensus statement on thediagnosis, treatment and follow-up of patients with primary ad-renal insufficiency. J Intern Med. 2014;275:104–115.

doi: 10.1210/jc.2015-1710 press.endocrine.org/journal/jcem 389

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